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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
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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
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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
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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
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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
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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
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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
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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
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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.
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