Antiviral Agents From Fungi : Diversity, Mechanisms and Potential Applications
Full text
This is a sel -a chi ed e sion o an o iginal a icle. This e sion
may di e om he o iginal in pagina ion and ypog aphic de ails.
Au ho (s):
Ti le:
Yea :
Ve sion:
Copy igh :
Righ s:
Righ s u l:
Please ci e he o iginal e sion:
CC BY 4.0
h ps://c ea i ecommons.o g/licenses/by/4.0/
An i i al Agen s F om Fungi : Di e si y, Mechanisms and Po en ial Applica ions
© 2018 Linnakoski, Reshamwala, Ve eli, Co ina-Esc ibano, Vanhanen and Ma jomäki
Published e sion
Linnakoski, Riikka; Reshamwala, Dhanik; Ve eli, Py y; Co ina-Esc ibano, Ma a;
Vanhanen, Hen i; Ma jomäki, Va pu
Linnakoski, R., Reshamwala, D., Ve eli, P., Co ina-Esc ibano, M., Vanhanen, H., & Ma jomäki, V.
(2018). An i i al Agen s F om Fungi : Di e si y, Mechanisms and Po en ial Applica ions.
F on ie s in Mic obiology, 9, A icle 2325. h ps://doi.o g/10.3389/ micb.2018.02325
2018
micb-09-02325 Oc obe 1, 2018 Time: 17:2 # 1
REVIEW
published: 02 Oc obe 2018
doi: 10.3389/ micb.2018.02325
Edi ed by:
Juan-Ca los Saiz,
Ins i u o Nacional de In es igación y
Tecnología Ag a ia y Alimen a ia
(INIA), Spain
Re iewed by:
Ul ike Lindequis ,
Uni e si y o G ei swald, Ge many
Taisuke Izumi,
Hen y M. Jackson Founda ion,
Uni ed S a es
*Co espondence:
Riikka Linnakoski
[email p o ec ed]
Special y sec ion:
This a icle was submi ed o
Vi ology,
a sec ion o he jou nal
F on ie s in Mic obiology
Recei ed: 03 July 2018
Accep ed: 11 Sep embe 2018
Published: 02 Oc obe 2018
Ci a ion:
Linnakoski R, Reshamwala D, Ve eli P,
Co ina-Esc ibano M, Vanhanen H
and Ma jomäki V (2018) An i i al
Agen s F om Fungi: Di e si y,
Mechanisms and Po en ial
Applica ions.
F on . Mic obiol. 9:2325.
doi: 10.3389/ micb.2018.02325
An i i al Agen s F om Fungi:
Di e si y, Mechanisms and Po en ial
Applica ions
Riikka Linnakoski1*, Dhanik Reshamwala2, Py y Ve eli1, Ma a Co ina-Esc ibano3,
Hen i Vanhanen3and Va pu Ma jomäki2
1Na u al Resou ces Ins i u e Finland (Luke), Helsinki, Finland, 2Di ision o Cell and Molecula Biology, Depa men
o Biological and En i onmen al Science, Nanoscience Cen e , Uni e si y o Jy äskylä, Jy äskylä, Finland, 3Na u al
Resou ces Ins i u e Finland (Luke), Joensuu, Finland
Vi al in ec ions a e amongs he mos common diseases a ec ing people wo ldwide.
New i uses eme ge all he ime and p esen ly we ha e limi ed numbe o accines and
only ew an i i als o comba i al diseases. Fungi ep esen a as sou ce o bioac i e
molecules, which could po en ially be used as an i i als in he u u e. He e, we ha e
summa ized he cu en knowledge o ungi as p oduce s o an i i al compounds and
discuss hei po en ial applica ions. In pa icula , we ha e in es iga ed how he an i i al
ac ion has been assessed and wha is known abou he molecula mechanisms and
ac ual a ge s. Fu he mo e, we highligh he impo ance o accu a e ungal species
iden i ica ion on an i i al and o he na u al p oduc s s udies.
Keywo ds: an i i al agen s, an i i al mechanisms, endophy es, ungal seconda y me aboli es, medicinal
mush ooms, na u al p oduc s
INTRODUCTION
Vi uses cause se ious ou b eaks in all con inen s leading o di icul symp oms and mo ali y, and
eno mous economic bu den o socie y. In addi ion, he cons an eme gence o new se o ypes in
i us g oups ha ha e a high mu a ion a e and low ideli y o i al eplica ion adds challenges in
comba ing agains hese i uses.
Vi uses can be di ided in o hose con aining a lipid en elope and hose whose genome is
only co e ed by a p o ein shell. En eloped i uses a e less s able and mo e p one o deg ada ion
when ea ed wi h lipid sol en s. Thei in ec ion mechanisms a e usually based on he p esence o
usogenic pep ides in he lipid en elope leading o a me ge o i al and cellula memb anes. The
non-en eloped i uses a e much mo e s able and may s ay ac i e in was ewa e s and on su aces
om se e al weeks o mon hs. The non-en eloped i uses such as No o i uses and en e o i uses
a e he e o e causing ou b eaks ha a e di icul o handle. In addi ion, hey show li le sensi i i y
o chemical disin ec an s (Wu zle and Saue b ei, 2004;Chan and Abu Baka , 2005). Thus, he e
is a need o bo h accines and an i i als o encoun e i al in ec ions. Howe e , he de elopmen
o accines agains a wide ange o newly eme ging i us se o ypes is challenging, and cu en ly
accines a e a ailable only agains a hand ul o i uses. In addi ion, accina ion canno help i he
in ec ion is al eady p esen in he sys em.
The an i i al d ugs inhibi he i us in ec ion ei he by speci ically a ge ing he i al p o eins
o he hos cellula ac o s ha he i uses exploi o hei ep oduc ion (Cle cq, 2002). Howe e ,
he p oblem in using i al p o eins as d ug a ge s is he high a e a which i uses p oduce mu an
esis an s ains agains hem (De Palma e al., 2008). Cellula ac o s exploi ed by i uses also se e
F on ie s in Mic obiology | www. on ie sin.o g 1Oc obe 2018 | Volume 9 | A icle 2325
micb-09-02325 Oc obe 1, 2018 Time: 17:2 # 2
Linnakoski e al. An i i al Agen s F om Fungi
as po en ial d ug a ge s. Howe e , hey canno be conside ed
au oma ically as eliable a ge s, since i uses may de ia e om
hei o iginal pa hway and s ill cause an e ec i e in ec ion (Van
de Linden e al., 2015). Also, a ge ing cellula ac o s migh
ha e an ad e se e ec on no mal unc ioning o he hos cells.
Fu he mo e, he mechanisms o non-en eloped i uses o b eak
he hos cell memb ane ba ie is less well known, which o ms an
addi ional challenge in de eloping s a egies agains hese i uses.
An an i i al d ug has o ul ill a se o p e equisi es when
unde going p eclinical and clinical ials. A i al equi emen
is ha he d ug should be e ec i e in inhibi ing he i us
in ec ion wi hou causing any cy o oxici y and wi h minimal
side e ec s o he hos cells. In addi ion, a d ug should be
able o comple ely inhibi he i us in ec ion, pa ial inhibi ion
leads o he gene a ion o d ug esis an mu an s ains. Due o
hese p e equisi es, only a hand ul o syn he ic an i i al d ugs
ha e made i pas he clinical phase. Un il oday, he success ul
‘one bug–one d ug’ app oach has been used o an i i al d ug
de elopmen . Howe e , oday he ocus has shi ed owa d
designing b oad-spec um an i i als, which can ac on mul iple
i uses by a ge ing a common bu essen ial i al unc ion (Vigan
e al., 2015). Combina o ial chemis y is nowadays a p e e ed
app oach adap ed by majo d ug companies o disco e ing
pha macologically signi ican compounds (S obel and Daisy,
2003). Al hough combina o ial chemis y app oach has p o en
success ul in op imizing s uc u es o d ug compounds, only one
de no o new chemical en i y (NCE) has been app o ed as a d ug
[so a enib (Nexa a ) ac ing as an i- umo ] in hese 25 plus yea s
om his me hod (C agg and Newman, 2007).
On he o he hand, bioac i e compounds isola ed om
na u al biological sou ces o e a as and unexplo ed di e si y
o chemical s uc u es, unma ched by e en he bigges
combina o ial da abases (S obel and Daisy, 2003). Since
housands o yea s, na u al p oduc s ha e se ed as adi ional
medicine and s ill p o ide he mos a o dable ea men o
diseases in many de eloping coun ies (Amza and Razum,
2018). A ound 40% o mode n d ugs and 49% o new chemical
p oduc s egis e ed by he Uni ed S a es Food and D ug
Adminis a ion (FDA) a e based on na u al p oduc s o hei
de i a i es (B ewe , 2000). Bioac i e compounds a e na u ally
de i ed me aboli es and/o by-p oduc s om mic oo ganisms,
plan s, o animals (Bake e al., 2000). Since he pas 25 yea s,
bioac i e compounds om many adi ional medicinal plan s
ha e been sc eened o hei an i i al ac i i y by a ious esea ch
g oups in Asia, Fa Eas , Eu ope, and Ame ica (Jassim and Naji,
2003).
Pa icula impo ance o no el d ug disco e ies has been
bioac i e molecules o ungal o igin. Especially ungi g owing in
unique en i onmen s such as endophy ic and ma ine ungi a e
being cons an ly explo ed o hei an ibac e ial and an i ungal
po en ial. Du ing he pas decade, many no el bioac i e
na u al p oduc s possessing cy o oxic, an icance , an ibac e ial
o an i ungal ac i i ies ha e been disco e ed om ma ine ungi
(Maye e al., 2013;Cheung e al., 2014;Singh e al., 2015). Fungi
po en ially con ain and/o p oduce se e al e ec i e molecules
ha could also be used as an i i als o o he hos s. The
disco e y and cha ac e iza ion o ungal compounds ha ing
an i i al ac i i ies is an eme ging ield o esea ch, and se e al
compounds ha e al eady been iden i ied as p omising. In his
e iew, we go h ough he p esen knowledge o ungi-de i ed
ex ac s and o he bioac i e agen s agains i al in ec ion. We
especially ocus on how he an i i al ac ion has been assessed and
how much is known abou he mechanisms o ac ion and ac ual
a ge s.
FUNGI AS A SOURCE OF ANTIVIRAL
AGENTS - AN OVERVIEW
The kingdom Fungi ep esen s a ich sou ce o a ious
biologically ac i e compounds. Du ing he pas decades,
housands o compounds wi h di e se biological ac i i ies
ha e been ecognized and con inue o be in es iga ed. Fungal
compounds wi h an i i al ac i i ies a e less ex ensi ely s udied,
bu also numbe o hese in es iga ions is on he inc ease. We
ha e compiled a lis o ungal o de s wi h epo ed posi i e
an i i al ac i i ies (Table 1) and also mapped his in o ma ion on
illus a i e phylogene ic ees (Figu es 1–3). Fungal species wi h
epo ed an i i al ac i i ies a e gi en in Supplemen a y Table S1.
These demons a e ha he p e ious s udies ha e ocused on
he la e-di e ging ungal phyla (Ascomyco a and Basidiomyco a)
and on a he limi ed axonomic g oups, while se e al emaining
comple ely unin es iga ed.
Pa icula ly well-s udied o hei biologically ac i e
compounds, including an i i als, a e edible and medicinal
mush ooms. Ano he g oup o ungi ha has been a ocus
o in e es a e endophy ic ungi, pa icula ly hose ha g ow
in ma ine habi a s. The biologically ac i e compounds can
be oughly di ided in o wo majo g oups o molecules; he
high-molecula weigh compounds p esen in he ex ac s
and p oduc s de i ed om he ui ing bodies o edible and
medicinal mush ooms, and he small o ganic molecules
(seconda y me aboli es) exc e ed by he endophy ic and o he
ungi in a liquid cul u ing ( e men a ion) se ups.
Fu he ough di ision can be made when conside ing he
epe oi e o an i i al compounds ound om di e en ungal
axonomic g oups. Mapping he an i i al compounds on he
la ge phylogeny o Fungi (Figu e 1) demons a es ha all he
cu en ly known seconda y me aboli es ha e been iden i ied
om Ascomyco a and Basidiomyco a. Ascomyco a wi h an i i al
ac i i ies includes endophy es and o he mic o ungi es ic ed
o limi ed numbe o o de s (Figu e 2), while he edible
and medicinal mush ooms in he Aga icales and Polypo ales
(Basidiomyco a) (Figu e 3) a e ecognized as a sou ce o
high-molecula weigh compounds. The inc easing numbe o
published ungal genome da a combined wi h he adi ional
bioac i i y sc eening me hods has p o ided no el insigh s
in o he ue capaci y o ungi as p oduce s o bioac i e
compounds (Be gmann e al., 2007;Khaldi e al., 2010;
B akhage, 2013;Cle ange e al., 2017). These s udies indica e
ha di e ences exis be ween hese wo phyla in a numbe
o seconda y me aboli es biosyn he ic gene clus e s and hei
dominance in hei genomes; basidiomyce es ypically ha ing
ewe compa ed o ascomyce es (B akhage, 2013). Howe e , he
F on ie s in Mic obiology | www. on ie sin.o g 2Oc obe 2018 | Volume 9 | A icle 2325
micb-09-02325 Oc obe 1, 2018 Time: 17:2 # 3
Linnakoski e al. An i i al Agen s F om Fungi
TABLE 1 | Fungal o de s wi h posi i e an i i al ac i i ies.
Phylum O de Vi us∗Re e ence
Ascomyco a Amphisphae iales EV711, HIV-I1Li e al., 2008;Wang J. e al., 2014;Jia e al., 2015
Capnodiales H1N11Peng e al., 2013;Wu e al., 2014
Chae o hy iales HIV-I4Ondeyka e al., 2003;Mlina ic e al., 2005
Diapo hales HIV-14, HSV-11Jayasu iya e al., 2003;Bunyapaiboons i e al., 2010
Do hideales HSV-15Isaka e al., 2007
Eu o iales EV712, DENV3, H1N12, HIV-14,
H3N22, JEV1, Zika i us2
Omu a e al., 1993;Ma suzaki e al., 1995;Singh e al., 2003a;Shiomi e al.,
2005;Sebas ian e al., 2011;Zhang e al., 2011;Gao e al., 2013a;He e al.,
2013;Bashyal e al., 2014;Fang e al., 2014;Peng e al., 2014;Wang J.-F.
e al., 2014;S ie le and S ie le, 2015;Yu e al., 2016;Raekiansyah e al., 2017
Glome ellales HIV-14Mlina ic e al., 2005
Helo iales HSV-11Rowley e al., 2003
Hypoc eales EV712, HIV-14, HSV-11,
H1N11,4,H3N21,4
Hazuda e al., 1999;Yoshimo o e al., 1999;Minagawa e al., 2002;Singh
e al., 2003a,b;Sawadjoon e al., 2004;Mlina ic e al., 2005;Jiang e al., 2011;
Ma e al., 2013;Li e al., 2014;Zhao e al., 2017;Pang e al., 2018
Mic oascales HIV-14Mlina ic e al., 2005
Ophios oma ales HIV-14Mlina ic e al., 2005
Pezizales HIV-14Pé ez e al., 2014
Pleospo ales HIV-14, HSV-11Hazuda e al., 1999;Singh e al., 2002;Guo e al., 2009;Shushni e al., 2011;
Bashyal e al., 2014;Zhang e al., 2015
Saccha omyce ales HIV-14Mlina ic e al., 2005
So daliales HIV-14, in luenza A and B4Mlina ic e al., 2005;Sac amen o e al., 2015
Xyla iales H1N12, HIV-14, HSV-11Hazuda e al., 1999;Pi ayakhajonwu e al., 2005;Zhang e al., 2016
Basidiomyco a Aga icales BoHV-11,3, H1N12, HCV5,
HBV4,5, HCV5, HIV-12,
HSV-11,2,3, HSV-21,2, in luenza
A2, polio2, RSV1,2, accinia1,
VS1, VZV2, WEE2
Kande e -Sze sze ´
n e al., 1980;Amo os e al., 1997;Saboula d e al., 1998;
Pi aino and B and , 1999;Wang and Ng, 2000, 2001;So imachi e al., 2001;
Lehmann e al., 2003;Chen e al., 2004;Mlina ic e al., 2005;B uggemann
e al., 2006;G inde e al., 2006;Faccin e al., 2007;Razumo e al., 2010;Zhu
e al., 2010;Ca dozo e al., 2011, 2014;Gao e al., 2013b;Yamamo o e al.,
2013;K upodo o a e al., 2014
Bole ales HIV-14, HSV-15, accinia1, VS1Kande e -Sze sze ´
n e al., 1980;Kanokmedhakul e al., 2003;Mlina ic e al.,
2005
Can ha ellales HIV-14, accinia1Kande e -Sze sze ´
n e al., 1980;Mlina ic e al., 2005
Gomphales accinia1Kande e -Sze sze ´
n e al., 1980
Hymenochae ales in luenza A and B4Ichimu a e al., 1998;Awadh Ali e al., 2003;
Polypo ales BoHV-11, EBV-A3, EV712,
H1N12, H3N22, HCV2,
HHV-12,4, HIV4, HSV-11,2,4,
HSV-21,2, in luenza A2,
MCMV1,2, measles2, mumps2,
polio1,2,3, PV-11, VSV2, WEE2,
EMCV2,4
Hi ose e al., 1987;Okada and Minamishima, 1987;Tochiku a e al., 1987,
1988;Suzuki e al., 1989;So imachi e al., 1990;Sa ka e al., 1993;Amo os
e al., 1997;Collins and Ng, 1997;El-Mekkawy e al., 1998;Min e al., 1998;
Eo e al., 1999a,b, 2000;Kim e al., 2000;Iwa suki e al., 2003;Mo hana e al.,
2003;Ngai and Ng, 2003;Singh e al., 2003a;Mlina ic e al., 2005;
Niede meye e al., 2005;Gu e al., 2007;El Dine e al., 2008;Sa o e al., 2009;
Razumo e al., 2010;Rincão e al., 2012;Teplyako a e al., 2012;
K upodo o a e al., 2014;Zhang e al., 2014;Ma suhisa e al., 2015;
Mize ska-Dudka e al., 2015
Russulales HIV-14, accinia1, VS1Kande e -Sze sze ´
n e al., 1980;Mlina ic e al., 2005;Wang e al., 2007
Ca ego ies o an i i al me hods used in he s udies: 1plague educ ion assay; 2CPE (cy opa hic e ec ) inhibi ion assay; 3mic oscope immuno luo escen assay; 4Speci ic
p o ease assay; 5o he . ∗WEE, Wes e n equine encaphili is; VZV, Va icella zos e ; RSV, espi a o y syncy ial i us; HCV, hepa i is C i us; HBV, hepa i is B i us;
MCMV, mu ine cy omegalo i us; VSV, esicula s oma i is i us; EBV, Eps ein-Ba i us; PV-1, polio i us 1; WNV, wes nile i us; HHV, human he pes i us; EMCV,
encephalomyoca di is i us; DENV, Dengue Vi us; JEV, Japanese encephali is i us.
epo ed di e ences be ween Ascomyco a and Basidiomyco a
e lec also o he bias om he di e en me hods ha ha e
been commonly used in sc eening hei biologically ac i e
compounds, no di e ences in hei ue a senals o bioac i e
compounds.
The mos ecen es ima es p edic ing ungal species di e si y
indica e ha only 3–8% o exis ing ungal species a e disco e ed
and desc ibed (Hawkswo h and Lücking, 2017). The e o e, he
ungi in es iga ed and ound o ha e po en ial posi i e an i i al
ac i i ies hus a ep esen only a minu e ac ion o hese
o ganisms and hei po en ial.
Edible and Medicinal Mush ooms
Mush ooms ha e been an impo an pa o ou die o cen u ies
due o hei nu i ional p ope ies. Thei ich con en in p o eins,
ca bohyd a es, mine als, i amins, unsa u a ed a y acids and
low alues o a and ene gy con en makes hem a aluable ood
F on ie s in Mic obiology | www. on ie sin.o g 3Oc obe 2018 | Volume 9 | A icle 2325
micb-09-02325 Oc obe 1, 2018 Time: 17:2 # 4
Linnakoski e al. An i i al Agen s F om Fungi
FIGURE 1 | A ee illus a ing he la ge phylogeny o Fungi shows ha he o igin o p esen ly known ungal-de i ed an i i al agen s (highligh ed) is es ic ed o he
la e-di e ging ungal phyla (Ascomyco a and Basidiomyco a). The igu e is cons uc ed based on phylogene ic ela ionships o Fungi on T ee o Li e Web P ojec
(h p:// olweb.o g). This ee is illus a i e and does no ep esen eal phylogene ic da a. Dashed lines: The g oup may no be monophyle ic, o phylogene ic posi ion
o he g oup is unce ain.
sou ce (Ba os e al., 2007, 2008;Ça˘
gla ı mak, 2007;Kalaˇ
c, 2009;
Ouzouni e al., 2009;Reis e al., 2012).
Some species p oducing conspicuous ui ing bodies ha e
a long his o y o medicinal use. Bioac i e compounds o he
ungal gene a which ha e had an impo an ole in adi ional
medicine, such as Ganode ma, ha e been subjec o ex ensi e
esea ch. Howe e , he e is a b oad numbe o o he edible
and medicinal species om di e en gene a conside ed o
be po en ial an i i al p ecu so s (Supplemen a y Table S1
and Figu e 3). The an i i al ac i i y o hese mush ooms is
associa ed mainly o he p esence o polysaccha ides in mycelium
and ui ing bodies, and syn hesis o i e penoid seconda y
me aboli es (Chen e al., 2012;Rincão e al., 2012). Howe e ,
la ge numbe o o he po en ially bioac i e compounds and/o
genes in ol ed in hei syn hesis has been epo ed (Shiao,
2003;Chen e al., 2012), indica ing ha he ull po en ial
o mush oom and medicinal ungi as a sou ce o bioac i e
compounds emains only pa ially unde s ood. P e ious s udy
has epo ed conside able di e ences in he con en s o bioac i e
compounds p oduced a di e en s ages o ungal li e cycle (Chen
e al., 2012), implying ha an i i al s udies need o ake in o
accoun he pheno ypic a ia ion and g ow h condi ions o he
ungal ma e ial.
Endophy es, Ma ine Fungi and Plan
Pa hogens
Endophy ic ungi ha inhabi abo e-g ound issues o heal hy
plan a leas pa o hei li e cycle a e highly di e se
in e ms o species ichness. These p ima ily ascomyce ous
(Ascomyco a) ungi common in all e es ial habi a s a e
conside ed o ha e impo an ecological oles in he e es ial
plan communi ies. Thei in e ac ions wi h hos plan s and
c oss- alk wi h o he endophy ic mic oo ganisms colonizing he
same plan a e complex and dynamic (Kusa i e al., 2012).
Endophy ic ungi ha e been ecognized as a ich sou ce o
seconda y me aboli es, which ole in he na u al habi a likely
include chemical signaling, de ense agains o he mic oo ganism,
and es ablishmen o symbiosis wi h hos plan (Schulz and
Boyle, 2005;Yim e al., 2007;Khaldi e al., 2010). Some also
mimic plan de ense compounds, and can, he e o e, p o ec hos
plan s agains he bi o es and pa hogens (Kusa i e al., 2012).
These seconda y me aboli es a e known o ha e g ea chemical
a ie y and nume ous biological ac i i ies wi h pha maceu ical
and bio echnological po en ial.
I has been hypo hesized ha ex eme habi a s ha bo g ea e
changes o no el d ug disco e y (Tha oi e al., 2013;Chá ez
e al., 2015). In e es ingly, ich ungal species di e si y inhabi s
ex eme en i onmen s such as deep-sea sedimen s and mang o e
ecosys ems (Kuma esan and Su yana ayanan, 2001;Mahé e al.,
2013). Many o ascomyce ous species ound in hese habi a s ha e
been disco e ed ha ing an i i al and o he biological ac i i ies
(Desmukh e al., 2018). The ex eme condi ions a e hough
o shape he seconda y me aboli e pa e ns o ungi, and hese
ungi a e ecognized as a pa icula ly p omising sou ce o di e se
and s uc u ally unp eceden ed no el compounds, which some
ha e al eady been s uc u ally cha ac e ized and se e al been
disco e ed o cons i u e o no el ca bon skele ons (Saleem e al.,
2007).
Howe e , also al eady ela i ely well-known ungi should
no be o e looked. Less in ensi ely in es iga ed ungi o hei
bioac i i ies include ee-pa hogens ha also seem p omising
F on ie s in Mic obiology | www. on ie sin.o g 4Oc obe 2018 | Volume 9 | A icle 2325
micb-09-02325 Oc obe 1, 2018 Time: 17:2 # 5
Linnakoski e al. An i i al Agen s F om Fungi
FIGURE 2 | In phylum Ascomyco a, an i i al agen s ha e been mainly iden i ied om endophy es and o he mic o ungi es ic ed o limi ed numbe o o de s. Highe
ed colo in ensi y indica es highe numbe o epo s in li e a u e. The igu e is cons uc ed based on phylogene ic ela ionships o Fungi on T ee o Li e Web P ojec
(h p:// olweb.o g). This ee is illus a i e and does no ep esen eal phylogene ic da a. IA, indole alkaloids; NRPS, non- ibosomal pep ides; PKS, polyke ides;
NRPS-PKS, hyb ids; T, e penoids; N/A, in o ma ion no a ailable. Dashed lines: The g oup may no be monophyle ic, o phylogene ic posi ion o he g oup is
unce ain.
sou ce o an i i al agen s. A p e ious s udy has de ec ed a numbe
o plan pa hogenic ungi wi h a ious ecological oles (whi e-
o ungi, so - o ungi, blue-s ain ungi and insec -symbion s)
ha ing an i i al ac i i ies (Mlina ic e al., 2005).
An i i al Resea ch and Fungal Taxonomy
Accu a e o ganism iden i ica ion is he basis o any biological
esea ch and i s applica ions. This is pa icula ly impo an o
bioac i e compounds aimed o pha maceu ical p oduc s. When
he physical ma e ial used is epo ed wi h a misapplied name,
he ep oducibili y o he s udy is e y low. Un o una ely,
in he li e a u e on bioac i i y and mechanisms o ac ion
o isola ed compounds o c ude ex ac s o ungal o igin,
epo ing on he me hods used o iden i y ungal ma e ials
e eals insensi i i y o he ele an axonomic discussion.
Me hodologically, only a mino i y o s udies ha e included
F on ie s in Mic obiology | www. on ie sin.o g 5Oc obe 2018 | Volume 9 | A icle 2325
micb-09-02325 Oc obe 1, 2018 Time: 17:2 # 6
Linnakoski e al. An i i al Agen s F om Fungi
FIGURE 3 | An i i al agen s epo ed om he phylum Basidiomyco a. Highe ed colo in ensi y indica es highe numbe o epo s in li e a u e. The igu e is
cons uc ed based on phylogene ic ela ionships o Fungi on T ee o Li e Web P ojec (h p:// olweb.o g). This ee is illus a i e and does no ep esen eal
phylogene ic da a. L, lignin de i a i e; PS, polysaccha ides; P, p o eins; C, polysaccha ide-p o ein/amino acid complex; NRPS, non- ibosomal pep ides; PKS,
polyke ides; T, e penoids; N/A, in o ma ion no a ailable. Dashed lines: The g oup may no be monophyle ic, o phylogene ic posi ion o he g oup is unce ain.
a combina ion o mo phological and molecula me hods o
species iden i ica ion (Raja e al., 2017). Gi en he ac ual
di e si y o kingdom Fungi, and he esul ing di icul ies in
delimi a ing species and gene a, as well as cons an disco e ies
o species new o science (Hawkswo h and Lücking, 2017),
anspa ency in his ma e is pa amoun . Long las ing deba es
among axonomis s, whe he o accep new names, spli ing
o an old species in o many new, o combina ions o old
names a e an e e yday a ai in he ield. This has in some
cases esul ed in conside able nomencla u al s a i ica ion,
highligh ing he need o engage axonomis s also in he s udy o
applica ions.
To illus a e his p oblem, we e alua ed li e a u e on one o
he mos commonly epo ed name appea ing in ungal an i i al
esea ch, ‘Ganode ma lucidum,’ as well as o he species in he
genus Ganode ma Ka s . The po oid, sap o ophic ungal species
G. lucidum (W. Cu . : F .) Ka s is an concise example o he
b oade issue. The adi ional medicinal use o Ganode ma spp.
in Eas Asia, Sou h-Eas Asia, and A ica has p omo ed in e es
in s udying he bioac i i y o hese ungi, wi h ‘G. lucidum’ o en
ci ed as he species o he ma e ial. Howe e , exac delimi a ion o
he species concep o G. lucidum, wi h a Eu opean ype locali y,
has been di icul due o lack o a holo ype specimen (S eyae ,
1972;Moncal o and Ry a den, 1997). A e mo phological and
F on ie s in Mic obiology | www. on ie sin.o g 6Oc obe 2018 | Volume 9 | A icle 2325
micb-09-02325 Oc obe 1, 2018 Time: 17:2 # 7
Linnakoski e al. An i i al Agen s F om Fungi
molecula phylogene ic s udies on he di e si y o he genus in
he pas decades (Moncal o e al., 1995;Cao e al., 2012;Zhou
e al., 2015), he consensus in he axonomic li e a u e is ha he
indus ially cul i a ed “Linghzi” and “Reishi” do no ep esen
he G. lucidum s. s , bu in ac o he species (Wang e al., 2009;
Cao e al., 2012). The e o e, ca e ul conside a ion is equi ed
when iden i ying such samples unde his name. He e, we lis ed
he epo ed me hods o acquisi ion and iden i ica ion used in
each an i i al s udy on Ganode ma (Supplemen a y Table S2).
As a summa y, ou o he 13 s udies, only ou used ma e ial ha
we can sa ely assume o ep esen he species decla ed, as a ungal
axonomis was being consul ed. In eigh cases i seems unlikely
gi en he sou cing o he ma e ials, bu could in p inciple be
e i ied o he con a y, assuming access o he o iginal ma e ial
in he ba ia. In one case, he expe imen al se -up is likely no
ep oducible due o ague desc ip ion o he ma e ial used, and
appa en lack o any p ese ed specimens. No s udies epo ed
sequence da a accession numbe s, no mo phological c i e ia
used o species de e mina ion. Va ious o ms o au ho ship,
including ou da ed and e oneous, we e p esen wi h he name
G. lucidum.
Whe he ungal ma e ial is in ac co ec ly iden i ied, has
consequences o he independen ep oducibili y o he s udy,
and e lec s also o unde s anding he species cha ac e is ics (i.e.,
equi emen s and pheno ypic a ia ion in a i icial cul i a ion
se ings). The e is ye a limi ed amoun o compa a i e wo k on
he di e ences be ween species and s ains o he composi ion in
he bioac i e compounds wi hin Ganode ma. The publica ions
a ailable a he momen indica e ha di e ences may be
conside able (Wel i e al., 2015;Hennicke e al., 2016), hough
assessmen s in o he ex en o occu ence o compounds o
in e es wi hin he genus is again con olu ed by he non-
anspa en epo ing o ma e ials (Rich e e al., 2015). In
conclusion, gi en he likelihood o misapplied names in he
li e a u e, ci ing s udies no epo ing iden i ica ion c i e ia as
e idence on he an i i al po en ial o G. lucidum s. s . needs o
ake his ambigui y in o accoun .
The misiden i ica ion o species and e en gene a is e en mo e
likely wi h mic oscopic ungi (such as endophy es) con aining
minu e and o e lapping mo phological cha ac e is ics, and o
which axonomy and di e si y emains widely unin es iga ed.
The e o e, we highligh he impo ance o anspa ency in
epo ing o used nomencla u e, physical ungal ma e ial and
me hod o iden i ica ion, which is pa amoun o he ad ancemen
o esea ch on an i i als om ungi. Fu he mo e, we encou age
he na u al p oduc esea ch communi y adop ing he ecen ly
sugges ed se o s anda dized p ocedu es o he iden i ica ion o
ungi (Raja e al., 2017).
O e iew o Me hods Assessing An i i al
Ac i i y
The mos widely used me hods o he ini ial sc eening o
ungal ex ac s o e alua e hei an i i al ac i i y a e he plaque
educ ion assay (Zhu e al., 2004;Faccin e al., 2007;Rincão
e al., 2012), cy opa hic e ec (CPE) assay (Liu e al., 2004;Zhang
e al., 2011) and immuno luo escence assay (Faccin e al., 2007)
(Table 2). In addi ion, a ious comme cially a ailable iabili y
assays moni o ing o , e.g., he cellula ATP le els ha e also been
used. These assays a e also used o pe o ming he ime o
addi ion s udies and in es iga ing he di ec i ucidal ac i i y o
he ungal ex ac s (Liu e al., 2004;Faccin e al., 2007).
All o hese me hods calcula e in di e en ways he iabili y o
he cells a e i us ac ion, and he an i i al ac i i y is moni o ed
as he escue o he cells om he i al in ec ion. The ead ou o
he plaque educ ion assay is he isual coun ing o he numbe o
plaques o med [plaques o ming uni (PFU)/ml] i.e., numbe o
uns ained “holes” in he cul u e pla e a e c ys al iole s aining
o he cells ha s ill adhe e on he pla e. This numbe is hen
used o calcula e he pe cen age o i al inhibi ion (% V.I.) (Zhu
e al., 2004). In immuno luo escence assay, he cells a e obse ed
unde mic oscope and ypically se e al hund eds o cells a e
sco ed. Fi s , he numbe o in ec ed cells is calcula ed om he
numbe o cells showing high abundance o i al capsid p o eins
p oduced in he cell cy oplasm (Ma jomäki e al., 2002). Then,
om he ob ained numbe , V.I. is calcula ed wi h espec o
un ea ed in ec ed cells (Faccin e al., 2007). In he case o CPE
assay, he ead ou is based on he spec opho ome ic abso bance
eading o he s ained iable cells, which is used o calcula e
he % V.I. (Liu e al., 2004). Typically, he iable cells le on
he bo om o he cul u e pla e and s ained wi h c ys al iole ,
a e dissol ed in he lysis bu e o p o ide a homogenous blue
suspension ha is easy o measu e in he spec opho ome e
(Schmid ke e al., 2001). The linea eg ession analysis o he plo s
o % V.I. is used o de e mine he 50% inhibi o y concen a ion
(IC50) which is used u he o calcula e he selec i i y index
(SI) (Rincão e al., 2012). The calcula ions a e also gi en he e as
o mulas:
% VI calcula ed om he plaque educ ion assay ead-ou =
[1−(numbe o plaques in es /numbe o plaques in i us
con ol)] ×100 (Rincão e al., 2012)
% VI calcula ed om he CPE assay ead-ou =
[(OD ) −(ODc) ]/[(ODc)mock −(ODc) ]
×100 (Liu e al., 2004)
whe e (OD ) is he op ical densi y (OD) o he cell, ea ed wi h
i us and bioex ac ( es ), (ODc) is he OD o he cell, ea ed
wi h i us ( i us con ol) and (ODc)mock is he OD o he mock
in ec ed cell (cell con ol).
SI =CC50/IC50
Whe e CC50 is 50% cy o oxic concen a ion, i.e., he
concen a ion which caused a 50% educ ion in he numbe o
iable cells o in he op ical densi y and IC50 is 50% inhibi o y
concen a ion, i.e., he concen a ion capable o educing 50%
PFU in ela ion o he con ols.
These abo e-men ioned me hods only a i m he an i i al
po en ial o bioac i e compounds and do no e eal any
in o ma ion ega ding hei mechanism o ac ion. Only ew
pape s ha e p og essed o e alua e he ac ual molecula a ge s.
In o de o s udy a ious i al o cellula a ge s o d ug ac ion,
se e al app oaches could be used. To s udy he di ec e ec on he
F on ie s in Mic obiology | www. on ie sin.o g 7Oc obe 2018 | Volume 9 | A icle 2325
micb-09-02325 Oc obe 1, 2018 Time: 17:2 # 8
Linnakoski e al. An i i al Agen s F om Fungi
TABLE 2 | Me hods used o e alua e an i i al e ec s.
To s udy Me hod Read ou Re e ence
An i i al ac i i y,
Vi ucidal ac i i y and
CPE assay using c ys al iole o s ain iable
cells
OD alues a 550–595 nm Schmid ke e al., 2001
Time o addi ion s udies Plaque educ ion assay No o plaques pe well−>PFU/ml Rincão e al., 2012
Mic oscopy immuno luo escen assay o label
newly syn he ized capsid p o eins
% o in ec ed cells wi h espec o un ea ed
in ec ed cells
Faccin e al., 2007
Di ec e ec on i us Nega i e s aining TEM Uns ained, in ac i uses s. da kly s ained,
emp y i uses
Myllynen e al., 2016
S uc u al s udies (e.g., x- ay c ys allog aphy o
c yo-EM)
A omis ical model exhibi ing d ug binding o
i us opening
De Colibus e al., 2014
Real- ime spec oscopy using SYBR-G een Fluo escence in ensi y inc ease upon genome
elease
Myllynen e al., 2016
Densi y g adien o adioac i ely labeled i us
showing in ac and uncoa ed i uses
Radioac i e coun s (CPM) pe each g adien
ac ion showing peaks o in ac and emp y
i uses
Ma jomäki e al., 2002;
Myllynen e al., 2016
Adso p ion/ ecep o
a achmen
Binding assay Radioac i e coun s (CPM) pe each g adien
ac ion showing peaks o in ac and emp y
i uses
Ma jomäki e al., 2002;
Myllynen e al., 2016
Compu a ional simula ions (molecula docking) Binding ene gy upon d ug binding (−kcal/mol) Zhang e al., 2014
Uncoa ing Densi y g adien o adioac i ely labeled i us
showing in ac and uncoa ed i uses
Radioac i e coun s (CPM) pe each g adien
ac ion showing peaks o in ac and emp y
i uses
Ma jomäki e al., 2002;
Myllynen e al., 2016
Real- ime spec oscopy
S uc u al s udies (e.g., x- ay c ys allog aphy o
c yo-EM)
Fluo escence in ensi y inc ease upon genome
elease
Myllynen e al., 2016
Hewa and Blaas, 2004;
Le y e al., 2010
Replica ion in e media es
( eplica ion) and capsid p o ein
p oduc ion ( ansla ion)
Immunolabeling and con ocal mic oscopy Fluo escence in ensi y quan i ica ion o capsid
o dsRNA p oduc ion
Ma ikainen e al., 2015
Speci ic i al p o eases HIV-1 p o ease pep ide clea age assay Moni o ing he luo escence o he enzyme
ca alyzed eac ion
Singh e al., 2004
X- ay c ys allog aphy A omis ic de ails o binding Singh e al., 2004
scin illa ion p oximi y assay (SPA) Measu ing adioac i i y o he enzyma ic
eac ion using adioac i e bio inyla ed subs a e
and s ep a idin agged scin illan
Guo e al., 2000
i us, he e a e se e al me hods ha could be employed. Fi s o
all, pe haps he easies way o see g oss e ec on he i us pa icle
is o nega i ely s ain he i us samples and obse e hem unde
ansmission elec on mic oscope (TEM) (Myllynen e al., 2016).
The e is a cha ac e is ic ea u e o dis inguish be ween in ac
i uses om emp y pa icles in TEM imaging. The s aining dye,
e.g., 2% U anyl ace a e o 1% phospho ungs ic acid canno en e
he capsid o in ac i uses because o which he in ac pa icles
appea b igh , i.e., uns ained, in TEM images (due o he con as
o he dye). Howe e , in case o emp y i uses, since he capsid is
open, he dye en e s he capsid and s ains he insides o he i us
hus gi ing a da k appea ance o emp y i us pa icles in TEM
images. Densi y g adien cen i uga ion o ei he adioac i ely
labeled o non-labeled i us is also insigh ul in e ealing he
di ec e ec o he ex ac on he i us (Ma jomäki e al., 2002;
Myllynen e al., 2016). The ead ou o adioac i e g adien
ac iona ion is he adioac i i y [coun s pe minu e (CPM)] o
a ious ac ions om di e en densi ies showing peaks o mo e
dense in ac i us and less dense emp y i uses o e en smalle
p oduc s like pen ame s. Di ec e ec s o bioac i e agen s should
show clea changes in he ac ion o in ac e sus emp y i uses.
The e ec on he i us a achmen on cellula ecep o s has
been s udied using binding assays. Binding is mos sensi i ely
s udied using adioac i ely labeled i us and by pe o ming
binding assays in cold, hence elimina ing he i us en y inside
he cells by endocy osis (Ma jomäki e al., 2002). Speci ic
e ec s o molecules in e e ing wi h ecep o binding ha e
been also pe o med in silico by using molecula docking
s udies (Zhang e al., 2014). Whe he he d ug a ge s he
i us uncoa ing in i o o while he i us is inside cellula
compa men s, can be e alua ed using eal- ime spec oscopy by
using RNA/DNA binding luo escen dyes (Myllynen e al., 2016)
and using adioac i e g adien ac iona ion s udies, espec i ely.
Radioac i ely labeled i us may be isola ed om he cells o
g adien ac iona ion which may e eal i he e is a block in
he i al genome elease, hus lea ing he i us as in ac o
longe pe iods. In o de o assess he e ec o bioex ac on he
e iciency o eplica ion and i al ansla ion, immuno luo escen
labeling may be pe o med ha e eals p oduc ion o i us capsid
p o eins and speci ic eplica ion in e media es, such as, e.g.,
dsRNA (Ma ikainen e al., 2015). Fu he mo e, qPCR o e eal
new i al RNA p oduc ion may be used.
F on ie s in Mic obiology | www. on ie sin.o g 8Oc obe 2018 | Volume 9 | A icle 2325
micb-09-02325 Oc obe 1, 2018 Time: 17:2 # 15
Linnakoski e al. An i i al Agen s F om Fungi
Cle cq, E. D. (2002). S a egies in he design o an i i al d ugs. Na . Re . 1, 13–25.
Cle ange , K. D., Bok, J. W., Ye, R., Miley, G. P., Ve dan, M. H., Velk, T., e al.
(2017). A scalable pla o m o iden i y ungal seconda y me aboli es and hei
gene clus e s. Na . Chem. Biol. 13, 895–905. doi: 10.1038/nchembio.2408
Collins, R. A., and Ng, T. B. (1997). Polysaccha opep ide om Co iolus e sicolo
has po en ial o use agains human immunode iciency i us ype 1 in ec ion.
Li e Sci. 60, 383–387. doi: 10.1016/S0024-3205(97)00294-4
C agg, G. M., and Newman, D. J. (2007). Na u al p oduc s as sou ces o new d ugs
o e he las 25 Yea s. J. Na . P od. 70, 461–477. doi: 10.1021/np068054
Cui, S. W. (2005). “S uc u al analysis o polysaccha ides,” in Food Ca bohyd a es,
ed. S. W. Cui (Boca Ra on, FL: CRC P ess), 105–160.
De Colibus, L. D., Wang, X., Spy ou, J. A. B., Kelly, J., Ren, J., G imes, J., e al.
(2014). Mo e-powe ul i us inhibi o s om s uc u e-based analysis o HEV71
capsid-binding molecules. Na . S uc . Mol. Biol. 21, 282–288. doi: 10.1038/
nsmb.2769
De Palma, A. M., Vliegen, I., De Cle cq, E., and Ney s, J. (2008). Selec i e inhibi o s
o pico na i us eplica ion. Med. Res. Re . 28, 823–884. doi: 10.1002/med.20125
Desmukh, S. K., P akash, V., and Ranjan, N. (2018). Ma ine ungi: a sou ce o
po en ial an icance compounds. F on . Mic obiol. 8:2536. doi: 10.3389/ micb.
2017.02536
El Dine, R. S., El Halawany, A. M., Ma, C.-M., and Ha o i, M. (2008). An i-HIV-
1 p o ease ac i i y o lanos ane i e penes om he Vie namese mush oom
Ganode ma colossum.J. Na . P od. 71, 1022–1026. doi: 10.1021/np8001139
El-Mekkawy, S., Meselhy, M. R., Nakamu a, N., Tezuka, Y., Ha o i, M.,
Kakiuchi, N., e al. (1998). An i-HIV-1 and an i-HIV-1-p o ease subs ances
om Ganode ma lucidum.Phy ochemis y 49, 1651–1657. doi: 10.1016/S0031-
9422(98)00254-4
Eo, S.-K., Kim, Y. S., Lee, C. K., and Han, S. S. (1999a). An ihe pe ic ac i i ies
o a ious p o ein bound polysaccha ides isola ed om Ganode ma lucidum.
J. E hnopha macol. 68, 175–181. doi: 10.1016/S0378-8741(99)00086-0
Eo, S.-K., Kim, Y.-O., Lee, C.-K., and Han, S.-S. (1999b). An i i al ac i i ies
o a ious wa e and me hanol soluble subs ances isola ed om Ganode ma
lucidum.J. E hnopha macol. 68, 129–136.
Eo, S.-K., Kim, Y. S., Lee, C. K., and Han, S. S. (2000). Possible mode o an i i al
ac i i y o acidic p o ein bound polysaccha ide isola ed om Ganode ma
lucidum on he pes simplex i us. J. E hnopha macol. 72, 475–481. doi: 10.1016/
S0378-8741(00)00266-X
Faccin, L. C., Bena i, F., Rincão, V. P., Man o ani, M. S., Soa es, S. A., Gonzaga,
M. L., e al. (2007). An i i al ac i i y o aqueous and e hanol ex ac s and o an
isola ed polysaccha ide om Aga icus b asiliensis agains polio i us ype 1. Le .
Appl. Mic obiol. 45, 24–28. doi: 10.1111/j.1472-765X.2007.02153.x
Fang, W., Lin, X., Zhou, X., Wan, J., Lu, X., Yang, B., e al. (2014). Cy o oxic
and an i i al ni obenzyl sesqui e penoids om he ma ine-de i ed ungus
Aspe gillus och aceus Jcma1F17. Med. Chem. Communn. 5, 701–705. doi: 10.
1039/C3MD00371J
Gao, H., Guo, W., Wang, Q., Zhang, L., Zhu, M., Zhu, T., e al. (2013a).
Aspul inones om a mang o e hizosphe e soil-de i ed ungus Aspe gillus
e eus Wwq-48 wi h an i-in luenza A i al (H1N1) ac i i y. Bioo gan. Med.
Chem. 23, 1776–1778. doi: 10.1016/j.bmcl.2013.01.051
Gao, W., Sun, Y., Chen, S., Zhang, J., Kang, J., Wang, Y., e al. (2013b). Mush oom
lec in enhanced immunogenici y o HBV DNA ca ine in C57BL/6 and
HbsAg- ansgenic mice. Vaccine 31, 2273—-2280. doi: 10.1016/j. accine.2013.
02.062
Ga gano, M., an G iens en, L., Isikhuemhen, O., Lindequis , U., Ven u ella, G.,
Wasse , S. P., e al. (2017). Medicinal mush ooms: aluable biological esou ces
o high exploi a ion po en ial. Plan Biosys . 151, 548–565. doi: 10.1080/
11263504.2017.1301590
Geoghegan, I., S einbe g, G., and Gu , S. (2017). The ole o ungal cell wall in
he in ec ion o plan s. T ends Mic obiol. 25, 957–967. doi: 10.1016/j. im.2017.
05.015
G inde, B., He land, G., and Johnson, E. (2006). E ec s on gene exp ession and i al
load o medicinal ex ac om Aga icus blazei in pa ien s wi h ch onic hepa i is
C in ec ion. In . Immunopha macol. 6, 1311–1314. doi: 10.1016/j.in imp.2006.
04.005
Gu, C.-Q., Li, J.-W., Chao, F., Jin, M., Wang, X.-W., and Shen, Z.-Q. (2007).
Isola ion, iden i ica ion and unc ion o a no el an i-HSV-1 p o ein om
G i ola ondosa.An i i al Res. 75, 250–257. doi: 10.1016/j.an i i al.2007.
03.011
Guo, B., Dai, J. R., Ng, S., Huang, Y., Leong, C., Ong, W., e al. (2000). Cy onic acids
A and B: no el idepside inhibi o s o hCMV p o ease om he endophy ic
ungus Cy onaema species. J. Na . P od. 63, 602–604. doi: 10.1021/np990467
Guo, H., Sun, B., Gao, H., Chen, X., Liu, S., Yao, X., e al. (2009). Dike opipe azines
om he Co dyceps-colonizing ungus Epicoccum nig um.J. Na . P od. 72,
2115–2119. doi: 10.1021/np900654a
Han, X., Chak abo i, A., Zhu, J., Liang, Z. X., and Li, J. (2016). Sequencing
and unc ional anno a ion o he whole genome o he ilamen ous ungus
Aspe gillus wes e diijkiae.BMC Genomics 17:633. doi: 10.1186/s12864-016-
2974-x
Ha ey, A. L., Ed ada-Ebel, R., and Quinn, R. J. (2015). The e-eme gence o
na u al p oduc s o d ug disco e y in he genomics e a. Na . Re . D ug Disco .
14, 111–129. doi: 10.1038/n d4510
Hawkswo h, D., and Lücking, R. (2017). Fungal di e si y e isi ed: 2.2 o
3.8 million species. Mic obiol. Spec . 5, FUNK-0052-2016. doi: 10.1128/
mic obiolspec.FUNK-0052-2016
Hazuda, D., Blau, C. U., Felock, P., Has ings, J., P amanik, B., Wol e, A., e al.
(1999). Isola ion and cha ac e iza ion o no el human immunode iciency i us
in eg ase inhibi o s om ungal me aboli es. An i i . Chem. Chemo he . 10,
63–70. doi: 10.1177/095632029901000202
He, F., Bao, J., Zhang, X.-Y., Tu, Z.-C., Shi, Y.-M., and Qi, S.-H. (2013).
Aspe e es ide A, a cy o oxic cyclic e apep ide om he ma ine-de i ed
ungus Aspe gillus e eus SCSGAF0162. J. Na . P od. 76, 1182–1186. doi: 10.
1021/np300897
Hennicke, F., Cheikh-Ali, Z., Liebisch, T., Maciá-Vicen e, J. G., Bode, H. B.,
and Piepenb ing, M. (2016). Dis inguishing comme cially g own Ganode ma
lucidum om Ganode ma lingzhi om Eu ope and Eas Asia on he basis o
mo phology, molecula phylogeny, and i e penic acid p o iles. Phy ochemis y
127, 29–37. doi: 10.1016/j.phy ochem.2016.03.012
Hewa , E. A., and Blaas, D. (2004). C yoelec on mic oscopy analysis o he
s uc u al changes associa ed wi h human hino i us ype 14 uncoa ing. J. Vi ol.
78, 2935–2942. doi: 10.1128/JVI.78.6.2935-2942.2004
Hi ose, K., Hakozaki, M., Kakuchi, J., Ma sunaga, K., Yoshikumi, C., Takahashi, M.,
e al. (1987). A biological esponse modi ie , PSK, inhibi s e e se ansc ip ase
in i o. Biochem. Biophys. Res. Commun. 149, 562–567. doi: 10.1016/0006-
291X(87)90404-9
Ho meis e , D., and Kelle , N. P. (2007). Na u al p oduc s o ilamen ous ungi:
enzymes, genes, and hei egula ion. Na . P od. Rep. 24, 393–416. doi: 10.1039/
B603084J
Hu, Y., Ahmed, S., Li, J., Luo, B., Gao, Z., Zhang, Q., e al. (2017). Imp o ed
ganode ic acids p oduc ion in Ganode ma lucidum by wood decaying
componen s. Sci. Rep. 7:46623. doi: 10.1038/s ep46623
Ichimu a, T., Wa anabe, O., and Mu uyama, S. (1998). Inhibi ion o HIV-1
p o ease by wa e -soluble lignin-like subs ance om an edible mush oom,
Fuscopo ia oblique.Biosci. Bio echnol. Biochem. 62, 575–577. doi: 10.1271/bbb.
62.575
Inglis, D. O., Binkley, J., Sk zypek, M. S., A naud, M. B., Ce quei a, G. C.,
and Shah, P. (2013). Comp ehensi e anno a ion o seconda y me aboli e
biosyn he ic genes and gene clus e s in Aspe gillus nidulans,A. umiga us,
A. nige and A. o yzae.BMC Mic obiol. 13:91. doi: 10.1186/1471-2180-13-91
Isaka, M., Be kaew, P., In e eya, K., Komwiji , S., and Sa hi kunanon, T. (2007).
An iplasmodial and an i i al cyclohexadepsipep ides om he endophy ic
ungus Pullula ia sp. BCC 8613. Te ahed on 29, 6855–6860. doi: 10.1016/j. e .
2007.04.062
Iwa suki, K., Akhisa, T., Tokuda, H., Ukiya, M., Oshikubo, M., Kimu a, Y., e al.
(2003). Lucidenic acids P and Q, me hyl lucidena e P, and o he i e penoids
om he ungus Ganode ma lucidum and hei inhibi o y e ec s o Eps ein-
Ba i us ac i a ion. J. Na . P od. 66, 1582–1585. doi: 10.1021/np0302293
Jassim, S. A., and Naji, M. A. (2003). No el an i i al agen s: a medicinal plan
pe spec i e. J. Appl. Mic obiol. 95, 412–427. doi: 10.1046/j.1365-2672.2003.
02026.x
Jayasu iya, H., Guan, Z., Polishook, J. D., Domb owski, A. W., Felock, P. J., Hazuda,
D. J., e al. (2003). Isola ion, s uc u e, and HIV-1 in eg ase inhibi o y ac i i y
o cy ospo ic acid, a ungal me aboli e p oduced by Cy ospo a sp. J. Na . P od.
66, 551–553. doi: 10.1021/np020533g
Jia, Y.-L., Guan, F.-F., Ma, J., Wang, C.-Y., and Shao, C.-L. (2015). Pes alo iolide
A, a new an i i al ph halide de i a i e om a so co al-de i ed ungus
Pes alo iopsis sp. Na . P od. Sci. 21, 227–230. doi: 10.20307/nps.2015.21.4.227
F on ie s in Mic obiology | www. on ie sin.o g 15 Oc obe 2018 | Volume 9 | A icle 2325
micb-09-02325 Oc obe 1, 2018 Time: 17:2 # 16
Linnakoski e al. An i i al Agen s F om Fungi
Jiang, Y., Wong, J. H., Ng, T. B., Liu, Z. K., Wang, C. R., Li, N., e al. (2011). Isola ion
o adenosine, iso-sinense in and dime hylguanosine wi h an ioxidan and HIV-
1 p o ease inhibi ing ac i i ies om ui ing bodies o Co dyceps mili a is.
Phy omedicine 18, 189–193. doi: 10.1016/j.phymed.2010.04.010
Kalaˇ
c, P. (2009). Chemical composi ion and nu i ional alue o Eu opean species
o wild g owing mush ooms: a e iew. Food Chem. 113, 9–16. doi: 10.1080/
10590500802350086
Kande e -Sze sze´
n, M., Kawechi, Z., Sała a, B., and Wi ek, M. (1980). Mush ooms
as a sou ce o subs ances wi h an i i al ac i i y. Ac a Mycol. 16, 215–220.
doi: 10.5586/am.1980.014
Kanokmedhakul, S., Kanokmedhakul, K., P ajuabsuk, T., Soy ong, K.,
Kongsae ee, P., and Suksam a n, A. (2003). A bioac i e i e penoid and
ulpinic acid de i a i es om he mush oom Scle ode ma ci inum.Plan a
Med. 69, 568–571. doi: 10.1055/s-2003-40639
Kelle , N. P., Tu ne , G., and Benne , J. W. (2005). Fungal seconda y me abolism
- om biochemis y o genomics. Na . Re . Mic obiol. 3, 937–947. doi: 10.1038/
n mic o1286
Khaldi, N., Sei uddin, F. T., Tu ne , G., Ha , D., Nie man, W. C., Wol e, K. H., e al.
(2010). SMURF: genomic mapping o ungal seconda y me aboli es. Fungal
Gene . Mic obiol. 47, 736–741. doi: 10.1016/j. gb.2010.06.003
Kim, Y.-S., Eo, S.-K., Oh, K.-W., Lee, C.-K., and Han, S.-S. (2000). An ihe pe ic
ac i i ies o acidic p o ein bound polysaccha ide isola ed om Ganode ma
lucidum alone and in combina ions wi h in e e ons. J. E hnopha macol. 72,
451–458. doi: 10.1016/S0378-8741(00)00263-4
K awczyk, E., Łuczak, M., Kobus, M., Ba´
nka, D., and Daniewski, W. (2003).
An i i al ac i i y o ?-benzoylphenylisose ina es o Lac a ius sesqui e penoid
alcohols in i o. Plan a Med. 69, 552–554. doi: 10.1055/s-2003-40649
K ohn, K., Bah amsa i, R., Flö ke, U., Ludewig, K., Kliche-Spo y, C., Michel, A.,
e al. (1997). Dihyd ocouma ins om ungi: isola ion, s uc u e elucida ion,
ci cula dich oism and biological ac i i y. Phy ochemis y 45, 313–320.
doi: 10.1016/S0031-9422(96)00854-0
K upodo o a, T., Rybalko, S., and Ba sh eyn, V. (2014). An i i al ac i i y o
Basidiomyce e mycelia agains in luenza ype A (se o ype H1N1) and he pes
simplex i us ype 2 in cell cul u e. Vi ol. Sin. 29, 284–290. doi: 10.1007/s12250-
014-3486-y
Kuma esan, V., and Su yana ayanan, T. S. (2001). Occu ence and dis ibu ion
o endophy ic ungi in a mang o e communi y. Mycol. Res. 105, 1388–1391.
doi: 10.1017/S0953756201004841
Kusa i, S., He weck, C., and Spi elle , M. (2012). Chemical ecology o endophy ic
ungi: o igins o seconda y me aboli es. Chem. Biol. 19, 792–798. doi: 10.1016/
j.chembiol.2012.06.004
Kusa i, S., Singh, S., and Jayabaska an, C. (2014a). Bio echnological po en ial o
plan -associa ed endophy ic ungi: hope e sus hype. T ends Bio echnol. 32,
297–303. doi: 10.1016/j. ib ech.2014.03.009
Kusa i, S., Singh, S., and Jayabaska an, C. (2014b). Re hinking p oduc ion o
Taxol∗(R) (pacli axel) using endophy e bio echnology. T ends Bio ehnol. 32,
303–311. doi: 10.1016/j. ib ech.2014.03.011
Lehmann, V. K. B., Huan, A., Ibanez-Cale o, S., Wilson, G. R., and Rineha ,
K. L. (2003). Illudin S, he sole an i i al compound in ma u e ui ing
bodies o Omphalo us illudens.J. Na . P od. 66, 1257–1258. doi: 10.1021/np0
30205w
Le y, H. C., Bos ina, M., Filman, D. J., and Hogle, J. M. (2010). Ca ching a i us in
he ac o RNA elease: a no el polio i us uncoa ing in e media e cha ac e ized
by c yo-elec on mic oscopy. J. Vi ol. 84, 4426–4441. doi: 10.1128/JVI.02393-09
Li, E., Tian, R., Liu, S., Chen, X., Guo, L., and Che, Y. (2008). Pes alo heols A-D,
bioac i e me aboli es om he plan endophy ic ungus Pes alo iopsis heae.
J. Na . P od. 71, 664–668. doi: 10.1021/np700744
Li, Y., Liu, D., Cen, S., P oksch, P., and Lin, W. (2014). Isoindolinone- ype
alkaloids om he sponge-de i ed ungus S achybo ys cha a um.Te ahed on
70, 7010–7015. doi: 10.1016/j. e .2014.07.047
Liu, J., Yang, F., Ye, L. B., Yang, X. J., Timani, K. A., Zheng, Y., e al. (2004).
Possible mode o ac ion o an ihe pe ic ac i i ies o a p o eoglycan isola ed om
he mycelia o Ganode ma lucidum in i o.J. E hnopha macol. 95, 265–272.
doi: 10.1016/j.jep.2004.07.010
Ma, X., Zhu, T., Ba, M., Li, G., Gu, Q., Guo, Y., e al. (2013). Phenylspi od imanes
wi h an i-HIV ac i i y om he sponge-de i ed ungus S achybo ys cha a um
MXH-X73. J. Na . P od. 76, 2298–2306. doi: 10.1021/np400683h
Mahé, S., Rédou, V., Cal ez, T. L., Vandenkoo nhuyse, P., and Bu gaud, G.
(2013). “Fungi in deep-sea en i onmen s and me agenomics,” in The Ecological
Genomics o Fungi, ed. F. Ma in (Hoboken, NJ: John Wiley & Sons Inc),
325–354. doi: 10.1002/9781118735893.ch15
Ma jomäki, V., Pie iäinen, V., Ma ilaien, H., Upla, P., I aska, J., Nissinen, L.,
e al. (2002). In e naliza ion o echo i us 1 in ca eolae. J. Vi ol. 76, 1856–1865.
doi: 10.1128/JVI.76.4.1856-1865.2002
Ma jomäki, V., Tu kki, P., and Hu unen, M. (2015). In ec ious en y pa hway o
En e o i us B species. Vi uses 7, 6387–6399. doi: 10.3390/ 7122945
Ma ikainen, M., Salo inne, K., Lah inen, T., Malola, S., Pe mi, P., Häkkinen, H.,
e al. (2015). Hyd ophobic pocke a ge ing p obes o En e o i uses. Nanoscale
7, 17457–17467. doi: 10.1039/c5n 04139b
Ma suhisa, K., Yamane, S., Okamo o, T., A a i, A., Kondoh, M., Ma suu a, Y.,
e al. (2015). An i-HVC e ec o Len inula edodes mycelia solid cul u e ex ac s
an low-molecula wi h lignin. Biochem. Biophys. Res. Communn. 462, 52–57.
doi: 10.1016/j.bb c.2015.04.104
Ma suzaki, K., Ikeda, H., Masuma, R., Tanaka, H., and Omu a, S. (1995).
Isoch omophilones I and II, no el inhibi o s agains gp120-CD4 binding
p oduced by Penicillium mul icolo FO-2338. J. An ibio . 48, 703–707.
doi: 10.7164/an ibio ics.48.703
Maye , A. M., Rod iguez, A. D., Tagliala ela-Sca a i, O., and Fuse ani, N. (2013).
Ma ine pha macology in 2009-2011: ma ine compounds wi h an ibac e ial,
an idiabe ic, an i ungal, an i-in lamma o y, an ip o ozoal, an i ube culosis, and
an i i al ac i i ies; a ec ing he immune and ne ous sys ems, and o he
miscellaneous mechanisms o ac ion. Ma . D ugs 11, 2510–2573. doi: 10.3390/
md11072510
Min, B.-S., Nakamu a, N., Miyashi o, H., Bae, K.-W., and Ha o i, M. (1998).
T i e penes om he spo es o Ganode ma lucidum and hei inhibi o y agains
HIV-1 p o ease. Chem. Pha m. Bull. 46, 1607–1612. doi: 10.1248/cpb.46.1607
Minagawa, K., Kouzoki, S., Yoshimo o, J., Kawamu a, Y., Tani, H., Iwa a, T., e al.
(2002). S achy lin and ace yls achy lin, no el an i-in luenza A i us subs ances,
p oduced by S achybo ys sp. RF-7260. I. Isola ion, s uc u e elucida ion
and biological ac i i ies. J. An ibio . 55, 155–164. doi: 10.7164/an ibio ics.
55.155
Mize ska-Dudka, M., Jaszek, M., Błachowicz, A., Rejczak, T. P., Ma u szewska, A.,
Osi´
nska-Ja oszuk, M., e al. (2015). Fungus Ce ena unicolo as an
e ec i e sou ce o new an i i al, immunomodula o y, and an icance
compounds. In . J. Biol. Mac omol. 79, 459–468. doi: 10.1016/j.ijbiomac.2015.
05.015
Mlina ic, A., Kac, J., and Pohle en, F. (2005). Sc eening o selec ed wood-damaging
ungi o he HIV-1 e e se ansc ip ase inhibi o s. Ac a Pha m. 55, 69–79.
Moncal o, J. M., and Ry a den, L. (1997). A Nomencla u al S udy o he
Ganode ma aceae Donk, Synopsis Fungo um 11. Oslo: Fungi lo a.
Moncal o, J. M., Wang, H. H., and Hseu, R. S. (1995). Gene phylogeny o he
Ganode ma lucidum complex based on ibosomal DNA sequences. Compa ison
wi h adi ional axonomic cha ac e s. Mycol. Res. 99, 1489–1499. doi: 10.1016/
S0953-7562(09)80798-3
Mo hana, R. A., Awadh Ali, N. A., Jansen, R., Wegne , U., Men el, R., and
Lindequis , U. (2003). An i i al lanos anoid i e penes om he ungus
Ganode ma p ei e i.Fi o e apia 74, 177–180. doi: 10.1016/S0367-326X(02)
00305-2
Myllynen, M., Kazme suk, A., and Ma jomäki, V. (2016). A no el open and
in ec ious o m o Echo i us 1. J. Vi ol. 90, 6759–6770. doi: 10.1128/JVI.
00342-16
Ngai, P. H., and Ng, T. B. (2003). Len in, a no el and po en an i ungal
p o ein om shi ake mush oom wi h inhibi o y e ec s on ac i i y o human
immunode iciency i us-1 e e se ansc ip ase and p oli e a ion o leukemia
cells. Li e Sci. 73, 3363–3374. doi: 10.1016/j.l s.2003.06.023
Niede meye , T. H., Lindequis , U., Men el, R., Gö des, D., Schmid , E.,
Thu ow, K., e al. (2005). An i i al e penoids cons i uen s o Ganode ma
p ei e i.J. Na . P od. 68, 1728–1731. doi: 10.1021/np0501886
Ochi, K., and Hosaka, T. (2013). New s a egies o d ug disco e y: ac i a ion o
silen o weakly exp essed mic obial gene clus e s. Appl. Mic obiol. Bio echnol.
97, 87–98. doi: 10.1007/s00253-012-4551-9
Okada, M., and Minamishima, Y. (1987). The e ec o biological esponse
modi ie s on ch onic and la en mu ine cy omegalo i us in ec ions. Mic obial.
Immunol. 31, 435–447. doi: 10.1111/j.1348-0421.1987. b03106.x
F on ie s in Mic obiology | www. on ie sin.o g 16 Oc obe 2018 | Volume 9 | A icle 2325
micb-09-02325 Oc obe 1, 2018 Time: 17:2 # 17
Linnakoski e al. An i i al Agen s F om Fungi
Omu a, S., Tanaka, H., Ma suzaki, K., Ikeda, H., and Masuma, R. (1993).
Isoch omophilones I and II, no el inhibi o s agains gp120-CD4 binding om
Penicillium sp. J. An ibio . 46, 1908–1911. doi: 10.7164/an ibio ics.46.1908
Ondeyka, J. G., Zink, D., Domb owski, A. W., Polishhook, J. D., Felock, P. J.,
Hazuda, D. J., e al. (2003). Isola ion, s uc u e and HIV-1 in eg ase inhibi o y
ac i i y o exophilic acid, a no el ungal me aboli es om Exophiala pisciphila.
J. An ibio . 56, 1018–1023. doi: 10.7164/an ibio ics.56.1018
Ouzouni, P. K., Pe idis, D., Kolle , W.-D., and Riganakos, K. A. (2009). Nu i ional
alue and me al con en o wild edible mush ooms collec ed om Wes
Macedonia and Epi us, G eece. Food Chem. 115, 1575–1580. doi: 10.1016/j.
oodchem.2009.02.014
Pang, X., Lin, X., Tian, Y., Liang, R., Wang, J., and Yang, B. (2018). Th ee
new polyke ides om he ma ine sponge-de i ed ungus T ichode ma sp.
SCSIO41004. Na . P od. Res. 32, 105–111. doi: 10.1080/14786419.2017.1338286
Peng, J., Lin, T., Wang, W., Xin, Z., Zhu, T., Gu, Q., e al. (2013). An i i al alkaloids
p oduced by he mang o e-de i ed ungus Cladospo ium sp. PJX-41. J. Na .
P od. 76, 1133–1140. doi: 10.1021/np400200k
Peng, J., Zhang, X., Du, L., Wang, W., Zhu, T., Gu, Q., e al. (2014). So bica echols
A and B, an i i al so bicillinoids om he ma ine-de i ed ungus Penicillium
ch ysogenum PJX-17. J. Na . P od. 77, 424–428. doi: 10.1021/np400977e
Pé ez, M., Sole -To on e as, R., Collado, J. A., Limones, C. G., Hells en, R.,
Johansson, M., e al. (2014). The ungal me aboli e galiellalac one in e e es wi h
he nuclea impo o NF-κB and inhibi s HIV- eplica ion. Chem. Biol. In e ac .
214, 69–75. doi: 10.1016/j.cbi.2014.02.012
Pi aino, F., and B and , C. R. (1999). Isola ion and pa ial cha ac e iza ion o an
an i i al, RC-183, om he edible mush oom Rozi es cape a a.An i i . Res. 43,
67–78. doi: 10.1016/S0166-3542(99)00035-2
Pi ayakhajonwu , P., Su annakad, R., Thienhi un, S., P abpai, S., Kongsae ee, P.,
and Tan icha oen, M. (2005). An an i-he pes simplex i us- ype 1 agen
om Xyla ia mellissii (BCC 1005). Te ahed on Le . 46, 1341–1344. doi:
10.1016/j. e le .2004.12.110
Posch, A. E., He wig, C., and Spadiu , O. (2013). Science-based biop ocess design
o ilamen ous ungi. T ends Bio echnol. 31, 37–44. doi: 10.1016/j. ib ech.2012.
10.008
Raekiansyah, M., Mo i, M., Nonaka, K., Agoh, M., Shiomi, K., Ma sumo o, A., e al.
(2017). Iden i ica ion o no el an i i al o ungus-de i ed b e eldin A agains
dengue i us. T op. Med. Heal h 45:32. doi: 10.1186/s41182-017-0072-7
Raja, H. A., Mille , A. N., Pea ce, C. J., and Obe lies, N. H. (2017). Fungal
iden i ica ion using molecula ools: a p ime o he na u al p oduc s esea ch
communi y. J. Na . P od. 80, 757–770. doi: 10.1021/acs.jna p od.6b01085
Razumo , I. A., Kosogo a, T. A., Kazachinskaia, E. I., Puchko a, L. I.,
Shche bako a, N. S., Go buno a, I. A., e al. (2010). An i i al ac i i y o aqueous
ex ac s and polysaccha ide ac ions om mycelium and ui bodies o highe
ungi. An ibio . Khimio e . 55, 14–18.
Reis, F. S., Ba os, L., Ma ins, A., and Fe ei a, I. C. (2012). Chemical composi ion
and nu i ional alue o he mos widely app ecia ed cul i a ed mush ooms:
an in e -species compa a i e s udy. Food. Chem. Toxicol. 50, 191–197.
doi: 10.1016/j. c .2011.10.056
Rich e , C., Wi s ein, C., Ki k, P. M., and S adle , M. (2015). An assessmen o
he axonomy and chemo axonomy o Ganode ma.Fungal Di e s. 71, 1–15.
doi: 10.1007/s13225-014-0313-6
Rincão, V. P., Yamamo o, K. A., Rica do, N. M., Soa es, S. A., Mei elles, L. D.,
Nozawa, C., e al. (2012). Polysaccha ides and ex ac s om Len inula edodes:
s uc u al ea u es and an i i al ac i i y. Vi ol. J. 15, 37. doi: 10.1186/1743-
422X-9-37
Rowley, D. C., Kelly, S., Kau man, C. A., Jensen, P. R., and Fenical, W.
(2003). Halo i s A-E, new an i i al agen s om ma ine-de i e ungus o he
genus Scy alidium.Bioo gan. Med. Chem. 11, 4263–4274. doi: 10.1016/S0968-
0896(03)00395-X
Saboula d, D., Gaspa , A., Roussel, B., and Villa d, J. (1998). New an ihe pe ic
nucleoside om a Basidiomyce e. C. R. Acad. Sci. 321, 585–591. doi: 10.1016/
S0764-4469(98)80461-7
Sac amen o, C. Q., Ma o elli, A., Fin elman-Rod igues, N., de F ei as,
C. S., de Melo, G. R., Rocha, M. E., e al. (2015). Au eoni ol, a ungi-
de i ed e ahyd o u an, inhibi s in luenza eplica ion by a ge ing i s su ace
glycop o ein hemagglu in. PLoS One 10:e0139236. doi: 10.1371/jou nal.pone.
0139236
Saleem, M., Ali, M. S., Hussain, S., Jabba , A., Ash a , M., and Lee, Y. S. (2007).
Ma ine na u al p oduc s o ungal o igin. Na . P od. Rep. 24, 1142–1152.
doi: 10.1039/b607254m
Sa ka , S., Koga, J., Whi ley, R. J., and Cha e jee, S. (1993). An i i al e ec o
he ex ac o cul u e medium o Len inus edodes mycelia on he eplica ion
o he pex simplex i us ype I. An i i al Res. 20, 293–303. doi: 10.1016/0166-
3542(93)90073-R
Sa o, N., Zhang, Q., Ma, C. M., and Ha o i, M. (2009). An i-human
immunode iciency i us-1 p o ease ac i i y o new lanos ane- ype i e penoids
om Ganode ma sinense.Chem. Pha m. Bull. 57, 1076–1080. doi: 10.1248/cpb.
57.1076
Sawadjoon, S., Ki akoop, P., Isaka, M., Madla, S., and Theb a anon h, Y. (2004).
An i i al and an iplasmodial spi odihyd obenzo u an e penes om he ungus
S achybo ys nephospo a.Plan a Med. 70, 1085–1087. doi: 10.1055/s-2004-
832652
Schmid ke, M., Schni le , U., Jahn, B., Dahse, H., and S elzne , A. (2001). A apid
assay o e alua ion o an i i al ac i i y agains coxsackie i us B3, in luenza
i us A, and he pes simplex i us ype 1. J. Vi ol. Me hods 95, 133–143.
doi: 10.1016/S0166-0934(01)00305-6
Schulz, B., and Boyle, C. (2005). The endophy ic con inuum. Mycol. Res. 109,
661–686. doi: 10.1017/S095375620500273X
Sebas ian, L., Madhusudana, S. N., Ra i, V., and Desai, A. (2011). Mycophenolic
acid inhibi s eplica ion o Japanese encephali is i us. Chemo he apy 57, 56–61.
doi: 10.1159/000321483
Shiao, M. S. (2003). Na u al p oduc s o he medicinal ungus Ganode ma lucidum:
occu ence, biological ac i i ies, and pha macological unc ions. Chem. Res. 3,
172–180.
Shiomi, K., Ma sui, R., Isozaki, M., Chiba, H., Sugai, T., Yamguchi, Y., e al.
(2005). Fungal phenalenones inhibi HIV-1 in eg ase. J. An ibio . 58, 65–68.
doi: 10.1038/ja.2005.8
Shushni, M. A., Singh, R., Men el, R., and Lindequis , U. (2011). Bal icolid: a new
12-membe ed mac olide wi h an i i al ac i i y om an Ascomyce ous ungus
o ma ine o igin. Ma . D ugs 9, 844–851. doi: 10.3390/md9050844
Singh, R. P., Kuma i, P., and Reddy, C. R. (2015). An imic obial compounds
om seaweeds-associa ed bac e ia and ungi. Appl. Mic obiol. Bio echnol. 99,
1571–1586. doi: 10.1007/s00253-014-6334-y
Singh, S. B., Ondeyka, J. G., Tsipou as, N., Ruby, C., Sa dana, V., Schulman, M.,
e al. (2004). Hinnuliquinone, a C2-symme ic dime ic non-pep ide ungal
me aboli e inhibi o o HIV-1 p o ease. Biochem. Biophys. Res. Commun. 324,
108–113. doi: 10.1016/j.bb c.2004.08.234
Singh, S. B., Zink, D. B., Quamina, D. S., Pelaez, F., Te an, A., Felock, P., e al.
(2002). In eg as a ins: s uc u e and HIV-1 in eg ase inhibi o y ac i i ies o wo
no el acemic e acyclic a oma ic he e ocycles p oduced by wo ungal species.
Te ahed on Le . 43, 2351–2354. doi: 10.1016/S0040-4039(02)00265-4
Singh, S. B., Jayasu iya, H., Dewey, R., Polishook, J. D., Domb owski, A. W.,
Zink, D. L., e al. (2003a). Isola ion, s uc u e, and HIV-1-in eg ase inhibi o y
ac i i y o s uc u ally di e se ungal me aboli es. J. Ind. Mic obiol. Bio echnol.
30, 721–731.
Singh, S. B., Zink, D. L., Domb owski, A. W., Polishook, J. D., Ondeyka, J. G.,
Hi sh ield, J., e al. (2003b). In eg acides: e acyclic i e penoid inhibi o s
o HIV-1 in eg ase p oduced by Fusa ium sp. Bioo g. Med. Chem. 11,
1577–1582.
So imachi, K., Ikeha a, Y., Maeza o, G., Okubo, A., Yamazaki, S., Akimo o, K.,
e al. (2001). Inhibi ion by Aga icus blazei Mu ill ac ions o cy opa hic
e ec induced by Wes e n Equine Encephali is (WEE) i us on VERO
cells in i o. Bioschi. Bio echnol. Biochem. 65, 1645–1647. doi: 10.1271/bbb.
65.1645
So imachi, K., Niwa, A., Yamazaki, A., Toda, S., and Yasumu a, Y. (1990). An i-
i al ac i i y o wa e -solubilized lignin de i a i es in i o.Ag ic. Biol. Chem.
54, 1337–1339. doi: 10.1007/s00253-014-6334-y
S eyae , R. L. (1972). Species o Ganode ma and ela ed gene a mainly o he Bogo
and Leiden He ba ia. Pe soonia 7, 55–118.
S ie le, A. A., and S ie le, D. B. (2015). Bioac i e seconda y me aboli es p oduced
by he ungal endophy es o coni e s. Na . P od. Communn. 10, 1671–1682.
S obel, G., and Daisy, B. (2003). Biop ospec ing o mic obial endophy es and
hei na u al p oduc s. Mic obiol. Mol. Biol. Re . 67, 491–502. doi: 10.1128/
MMBR.67.4.491-502.2003
F on ie s in Mic obiology | www. on ie sin.o g 17 Oc obe 2018 | Volume 9 | A icle 2325
micb-09-02325 Oc obe 1, 2018 Time: 17:2 # 18
Linnakoski e al. An i i al Agen s F om Fungi
Suzuki, H., Okubo, A., Yamazuki, S., Suzuki, K., Mi suya, H., and Toda, S. (1989).
Inhibi ion o he in ec i i y and cy opa hic e ec o human immunode iciency
i us by wa e -soluble lignin in an ex ac o he cul u e medium o Len inus
edodes mycelia (LEM). Biochem. Biophys. Res. Commun. 160, 367–373.
doi: 10.1016/0006-291X(89)91665-3
Teplyako a, T. V., Psu se a, N. V., Kosogo a, N. V., Mazu ko a, T. A., Khanin,
V. A., and Viasenko, V. A. (2012). An i i al ac i i y o polypo oid mush ooms
(highe Basidiomyce es) om Al ai Moun ains (Russia). In . J. Med. Mush ooms
14, 37–45. doi: 10.1615/In JMedMush . 14.i1.40
Tha oi, H., Behe a, B. C., and Mish a, R. R. (2013). Ecological ole and
bio echnological po en ial o mang o e ungi: a e iew. Mycology 4, 54–71.
Tochiku a, T. S., Nakashima, H., Hi ose, K., and Yamamo o, N. (1987). A biological
esponse modi ie , PSK, inhibi s human immunode iciency i us in ec ion
in i o.Biochem. Biophys. Res. Commun. 2, 726–733. doi: 10.1016/0006-
291X(87)90936-3
Tochiku a, T. S., Nakashima, H., Ohashi, Y., and Yamamo o, N. (1988). Inhibi ion
(in i o) o eplica ion and o he cy opa hic e ec o human immunode iciency
i us by an ex ac o he cul u e medium o Len inus edodes mycelia. Med.
Mic obiol. Immunol. 177, 235–244. doi: 10.1007/BF00189409
Van de Linden, L., Wol he s, K. C., and an Kuppe eld, F. J. (2015). Replica ion
and inhibi o s o En e o i uses and pa echo i uses. Vi uses 7, 4529–4562.
doi: 10.3390/ 7082832
Vigan , F., San os, N. C., and Lee, B. (2015). B oad-spec um an i i als agains i al
usion. Na . Re . Mic obiol. 13, 426–437. doi: 10.1038/n mic o3475
Wang, D.-M., Wu, S.-H., Su, C.-H., Peng, J.-T., Shih, Y.-H., and Chen, L.-C. (2009).
Ganode ma mul ipileum, he co ec name o ‘G. lucidum’ in opical Asia. Bo .
S ud 50, 451–458.
Wang, H., and Ng, T. B. (2000). Isola ion o a no el ubiqui in-like p o ein
om Pleu o us os ea us mush oom wi h an i-human immunode?ciency i us,
ansla ion-inhibi o y, and ibonuclease ac i i ies. Biochem. Biophys. Res.
Commun. 276, 587–593. doi: 10.1006/bb c.2000.3540
Wang, H., and Ng, T. B. (2001). Isola ion and cha ac e iza ion o elu in, a no el
low-molecula -weigh ibosome-inac i a ing p o ein om win e mush oom
(Flammulina elu ipes) ui ing bodies. Li e Sci. 68, 2151–2158. doi: 10.1016/
S0024-3205(01)01023-2
Wang, J., Wang, H. X., and Ng, T. B. (2007). A pep ide wi h HIV-1 e e se
ansc ip ase inhibi o y ac i i y om he medicinal mush oom Russula
paludosa.Pep ides 28, 560–565. doi: 10.1016/j.pep ides.2006.10.004
Wang, J., Wei, X., Lu, X., Lu, X., Wan, J., Lin, X., e al. (2014). Eigh new
polyke ide me aboli es om he ungus Pes alo iopsis accinii endogenous wi h
he mang o e plan Kandelia candel (L.) D uce. Te ahed on 70, 9695–9701.
doi: 10.1016/j. e .2014.10.056
Wang, J.-F., Lin, X.-P., Qin, C., Liao, S.-R., Wan, J.-T., Zhang, T. Y., e al. (2014).
An imic obial and an i i al sesqui e penes om sponge-de i ed ungus,
Aspe gillus sydowii ZSDS1-F6. J. An ibio . 67, 581–583. doi: 10.1038/ja.2014.97
Wel i, S., Mo eau, P.-A., Decock, C., Danel, C., Duhal, N., Fa el, A., e al.
(2015). Oxygena ed lanos ane- ype i e penes p o iling in lacca e Ganode ma
chemo axonomy. Mycol. P og. 14:45. doi: 10.1007/s11557-015-1066-7
Wu, D.-T., Deng, Y., Chen, L.-X., Zhao, J., Bzhelyansky, A., and Li, S.-P. (2017).
E alua ion on quali y consis ency o Ganode ma lucidum die a y supplemen s
collec ed in he Uni ed S a es. Sci. Rep. 7:7792. doi: 10.1038/s41598-017-
06336-3
Wu, G., Sun, X., Yu, G., Wang, W., Zhu, T., Gu, Q., e al. (2014). Cladosins
A-E, hyb id polyke ides om a deep-sea-de i ed ungus, Cladospo ium
sphae ospe mum.J. Na . P od. 77, 270–275. doi: 10.1021/np400833x
Wu zle , P., and Saue b ei, A. (2004). Vi ucidal ac i i y o he new disin ec an
monope ci ic acid. Le . Appl. Mic obiol. 39, 194–198. doi: 10.1111/j.1472-
765X.2004.01561.x
Yamamo o, K. A., Galha di, L. C., Rincão, V. P., Soa es Sde, A., Rica do, N. M.,
Nozawa, C., e al. (2013). An ihe pe ic ac i i y o an Aga icus b asiliensis
polysaccha ide, i s sul a ed de i a i e and ac ions. In . J. Biol. Mac omol. 52,
9–13. doi: 10.1016/j.ijbiomac.2012.09.029
Yim, G., Wang, H. H., and Da ies, J. (2007). An ibio ics as signaling molecules.
Philos. T ans. Soc. B 362, 1195–1200. doi: 10.1098/ s b.2007.2044
Yoshimo o, J., Kakui, M., Iwasaki, H., Fujiwa a, T., Sugimo o, H., and Ha o i, N.
(1999). Iden i ica ion o a no el HA con o ma ional change inhibi o o
human in luenza i us. A ch. Vi ol. 144, 865–878. doi: 10.1007/s0070500
50552
Yu, G., Zhou, G., Zhu, M., Wang, W., Gu, Q., and Li, D. (2016). Neosa o yadins A
and B, umiquinazoline alkaloids om a mang o e-de i ed ungus Neosa o ya
udagawae HDN13-313. O g. Le . 18, 244–247. doi: 10.1021/acs.o gle .
5b02964
Zhang, D., Tao, X., Chen, R., Liu, J., Fang, X., Yu, L., e al. (2015). Pe icoannosin A,
a polyke ide syn hase-non ibosomal pep ide syn he ase hyb id me aboli e wi h
new ca bon skele on om he endophy ic ungus Pe iconia sp. O g. Le . 17,
4304–4307. doi: 10.1021/acs.o gle .5b02123
Zhang, G., Sun, S., Zhu, T., Lin, Z., Gu, J., Li, D., e al. (2011). An i i al isoindolone
de i a i es om an endophy ic ungus Eme icella sp. associa ed wi h Aegice as
co nicula um.Phy ochemis y 72, 1436–1442. doi: 10.1016/j.phy ochem.2011.
04.014
Zhang, S. P., Huang, R., Li, F. F., Wei, H. X., Fang, X. W., Xie, X. S., e al.
(2016). An i i al an h aquinones and azaphilones p oduced by an endophy ic
ungus Nig ospo a sp. om Aconi um ca michaeli.Fi o he apia 112, 85–89.
doi: 10.1016/j. i o e.2016.05.013
Zhang, W., Tao, J., Yang, X., Zhang, J., Lu, H., Wu, K., e al. (2014). An i i al
e ec s o wo Ganode ma lucidum i e penoids agains en e o i us 71
in ec ion. Biochem. Biophys. Communn. 449, 307–312. doi: 10.1016/j.bb c.2014.
05.019
Zhao, J., Lu, J., Shen, Y., Tan, Z., Zhang, M., Chen, R., e al. (2017). S achybo ysams
A-E, p enyla ed isoindolinone de i a i es wi h an i-HIV ac i i y om he
ungus S achybo ys cha a um.Phy ochem. Le . 20, 289–294. doi: 10.1016/j.
phy ol.2017.04.031
Zhou, L.-W., Cao, Y., Wu, S.-H., Vlasák, J., Li, D. W., Li, M. J., e al. (2015). Global
di e si y o he Ganode ma lucidum complex (Ganode ma aceae, Polypo ales)
in e ed om mo phology and mul ilocus phylogeny. Phy ochemis y 114,
7–15. doi: 10.1016/j.phy ochem.2014.09.023
Zhou, S., Gao, Y., and Chan, E. (2005). Clinical ials o medicinal mush ooms:
expe ience wi h Ganode ma lucidum (W.Cu .:F .) Lloyd (Lingzhi Mush oom).
In . J. Med. Mush ooms 7, 111–118. doi: 10.1615/In JMedMush . 7.
i12.110
Zhu, W., Chiu, L., Ooi, V. E., Chan, P. K., and Ang, P. O. J . (2004). An i i al
p ope y and mode o ac ion o a sulpha ed polysaccha ide om Sa gassum
pa ens agains he pes simplex i us ype 2. In . J. An imic ob. Agen s 24, 81–85.
doi: 10.1016/j.ijan imicag.2004.02.022
Zhu, Y.-C., Wang, G., Yang, X.-L., Luo, D.-Q., Zhu, Q.-C., Peng, T., e al. (2010).
Ag ocybone, a no el bis-sesqui e pene wi h a spi odienone s uc u es om
basidiomyce es Ag ocybe salicacola.Te ahed on Le . 51, 3443–3445. doi: 10.
1016/j. e le .2010.04.128
Con lic o In e es S a emen : The au ho s decla e ha he esea ch was
conduc ed in he absence o any comme cial o inancial ela ionships ha could
be cons ued as a po en ial con lic o in e es .
Copy igh © 2018 Linnakoski, Reshamwala, Ve eli, Co ina-Esc ibano, Vanhanen
and Ma jomäki. This is an open-access a icle dis ibu ed unde he e ms o
he C ea i e Commons A ibu ion License (CC BY). The use, dis ibu ion o
ep oduc ion in o he o ums is pe mi ed, p o ided he o iginal au ho (s) and he
copy igh owne (s) a e c edi ed and ha he o iginal publica ion in his jou nal
is ci ed, in acco dance wi h accep ed academic p ac ice. No use, dis ibu ion o
ep oduc ion is pe mi ed which does no comply wi h hese e ms.
F on ie s in Mic obiology | www. on ie sin.o g 18 Oc obe 2018 | Volume 9 | A icle 2325