Targeting Multiple Signal Transduction Pathways of SARS-CoV-2: Approaches to COVID-19 Therapeutic Candidates

molecules Review Targeting Multiple Signal Transduction Pathways of SARS-CoV-2: Approaches to COVID-19 Therapeutic Candidates Sajad Fakhri 1,† , Zeinab Nouri 2,† , Seyed Zachariah Moradi 1,3 , Esra Küpeli Akkol 4, Sana Piri 1, Eduardo Sobarzo-Sánchez 5,6,* , Mohammad Hosein Farzaei 7,* and Javier Echeverría8,*   Citation: Fakhri, S.; Nouri, Z.; Moradi, S.Z.; Akkol, E.K.; Piri, S.; Sobarzo-Sánchez, E.; Farzaei, M.H.; Echeverría, J. Targeting Multiple Signal Transduction Pathways of SARS-CoV-2: Approaches to COVID-19 Therapeutic Candidates. Molecules 2021,26, 2917. https:// doi.org/10.3390/molecules26102917 Academic Editor: Kyoko Nakagawa-Goto Received: 18 March 2021 Accepted: 11 May 2021 Published: 14 May 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran; pharmacy[email protected] (S.F.); [email protected] (S.Z.M.); [email protected] (S.P.) 2Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah 6714415153, Iran; [email protected] 3Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran 4Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Etiler, Ankara 06330, Turkey; [email protected] 5Instituto de Investigación y Postgrado, Facultad de Ciencias de la Salud, Universidad Central de Chile, Santiago 8330507, Chile 6Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain 7Medical Technology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran 8 Departamento de Ciencias del Ambiente, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago 9170022, Chile *Correspondence: [email protected] (E.S.-S.); [email protected] (M.H.F.); javier[email protected] (J.E.) † The authors have contributed equally to this review. Abstract: Due to the complicated pathogenic pathways of coronavirus disease 2019 (COVID-19), related medicinal therapies have remained a clinical challenge. COVID-19 highlights the urgent need to develop mechanistic pathogenic pathways and effective agents for preventing/treating future epidemics. As a result, the destructive pathways of COVID-19 are in the line with clinical symptoms induced by severe acute coronary syndrome (SARS), including lung failure and pneumonia. Accordingly, revealing the exact signaling pathways, including inflammation, oxidative stress, apoptosis, and autophagy, as well as relative representative mediators such as tumor necrosis factorα (TNFα ), nuclear factor erythroid 2-related factor 2 (Nrf2), Bax/caspases, and Beclin/LC3, respectively, will pave the road for combating COVID-19. Prevailing host factors and multiple steps of SARS-CoV-2 attachment/entry, replication, and assembly/release would be hopeful strategies against COVID-19. This is a comprehensive review of the destructive signaling pathways and host–pathogen interaction of SARS-CoV-2, as well as related therapeutic targets and treatment strategies, including potential natural products-based candidates. Keywords: coronavirus; SARS-CoV-2; COVID-19; signaling pathway; inflammation; oxidative stress; apoptosis; autophagy; natural products 1. Introduction As a global pandemic, an outbreak of novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), caused the coronavirus disease 2019 (COVID-19). It has been a serious leading cause of morbidity and mortality worldwide [ 1 , 2 ]. Coronaviruses (CoVs) are a group of single-stranded enveloped ribonucleic acid viruses Molecules 2021,26, 2917. https://doi.org/10.3390/molecules26102917 https://www.mdpi.com/journal/molecules Molecules 2021,26, 2917 2 of 32 which are classified into four genera, including α , β , γ , and δ . In the past two decades, two members of the β -CoVs with a zoonotic origin, including SARS-CoV and Middle East Respiratory Syndrome (MERS)-CoV, caused two epidemics in China during 2002–2003 and in the Middle East in 2012, respectively [3–5]. The clinical manifestations of COVID-19 mainly encompass pneumonia-related symptoms, such as fever, cough, and shortness of breath [ 6 ]. In severe patients, it would lead to acute respiratory distress syndrome (ARDS), cardiovascular, neurological, hepatic, renal, and gastrointestinal complications [ 7 , 8 ], which all seemed to be correlated with dysregulated mechanisms. It has been well-established that the SARS-CoV-2 genome is closely related to the first SARS-CoV [ 9 ]. The underlying mechanisms by which SARS-CoV-2 elicits its detrimental effects remained unclear; however, possible mechanisms encompass inflammation, oxidative stress, apoptosis, autophagy, and the processes associated with virus entry into host cells, such as the endocytic pathway and angiotensin-converting enzyme 2 (ACE2) pathway [ 8 , 10 – 12 ]. As of yet, no specific antiviral drug has been discovered for SARS-CoV-2; hence, extensive studies have been ignited to find effective drugs for targeting the aforementioned pathways and for combating COVID-19. In light of the outbreak, several non-specific medications have been exploited, such as broad-spectrum antiviral, anti-inflammatory, antioxidant, and antiapoptotic therapies, immunotherapeutic agents, antibiotics, and supportive care such as supplementary oxygen [ 13 – 15 ]. Despite advancements in providing antiviral drugs, their associated toxicity and high financial costs are a significant hurdle in their clinical applications [ 16 ]. Therefore, there exists a dire need to discover new, safe, and more efficacious treatment alternatives to achieve successful healing therapies. In recent reviews, the role of oxidative stress [ 17 ], inflammation [ 18 , 19 ], and some host factors [ 20 ] were developed separately, with no focus on all the therapeutic agents, therapeutic targets, host–pathogen interaction, and dysregulated signaling pathways involved in the pathogenesis of SARS-CoV-2. In the present review, we describe the dysregulated signaling pathways and host–pathogen interaction of SARS-CoV-2, as well as relative therapeutic targets and treatment strategies, concentrating on oxidative stress, inflammation, apoptosis, autophagy, the immune system, and virus life cycle. 2. COVID-19: Genetics and Structure SARS-CoV-2 is a single-stranded enveloped ribonucleic acid virus with a genome size of 29,903 nucleotides [ 21 ]. This single strand of RNA is covered by a phosphorylated capsid protein which, together, both form a nucleocapsid. Phospholipid bilayers shield the nucleocapsid and are coated by spike glycoprotein and, probably, hemagglutinin-esterase protein [ 22 ]. The virus genome is comprised of two untranslated regions (UTRs) at the 5 0 and 3 0 ends, which constitute 265 and 358 nucleotides, respectively, as well as 11 open reading frames (ORFs) that encode 27 structural, non-structural, as well as accessory proteins [ 23 , 24 ]. Two overlapping ORF 1a and 1b contain two-thirds of the genome and encode 16 non-structural proteins (NSPs) within the pp1ab gene. These proteins comprise NSP3 (papain-like), NSP5 (3C-like protease domain), NSP12 (RNA-dependent RNA polymerase), NSP13 (helicase), NSP14 (3 0 –5 0 exonuclease), as well as other NSPs that are engaged with the transcription and replication of the viral genome [25,26]. The remaining ORFs code structural proteins including spike protein (S), envelopes protein (E), membrane protein (M), as well as nucleocapsid protein (N), and at least six accessory proteins such as orf3a, orf6, orf7a, orf7b, orf8, and orf10 [ 27 ]. In some cases, the hemagglutinin esterase gene proposed to increase the virus entry mediated to S protein has been located between ORF1b and ORF S [28]. 3. Clinical Features of COVID-19 Disease Most patients infected with SARS-CoV-2 exhibit respiratory complications such as pneumonia and ARDS. ARDS is a common leading cause of death in patients with COVID-19 , which is characterized by pulmonary and interstitial tissue devastation [ 29 ]. Molecules 2021,26, 2917 3 of 32 The genetic material of SARS-CoV-2 has been identified in cerebrospinal fluid, indicating that SARS-CoV-2 can directly attack the central nervous system, which contributes to several neurological damages. This procedure develops neurological complications, including headache, encephalitis, impaired consciousness, epilepsy, taste/smell disorders, and nausea/vomiting [ 30 – 32 ]. SARS-CoV-2 exploits neuronal pathways, such as the olfactory pathway and blood circulation pathway, to enter the nervous system [ 33 – 35 ]. During SARS-CoV-2 infection, impairment of the respiratory gaseous exchange leads to hypoxia and anaerobic metabolism, as well as acidic conditions in the brain, which, in turn, participate in cerebral edema and occlusion of the cerebral circulation, and subsequently lead to headache and acute cerebrovascular disease [ 36 ]. SARS-CoV-2 also exerts its deleterious effects on the nervous system through an intracranial cytokine storm [ 37 ]. Activation of macrophages, microglia, and astrocytes enhances the release of pro-inflammatory cytokines and provokes nerve degeneration and the apoptotic death of neuronal cells [ 38 ]. A growing number of patients infected with SARS-CoV-2 manifest signs or symptoms of liver dysfunction that can be attributed to the respiratory distress syndrome-induced hypoxia and the release of huge circulating detrimental inflammatory mediators with the ability to invade liver cells, causing hepatocyte damage and elevated liver enzymes [ 39 ]. Additionally, the downregulation of ACE2 by SARS-CoV-2 may enhance blood pressure, and thereby elevate the risk of intracranial hemorrhage [40]. A growing number of patients infected with SARS-CoV-2 manifested signs of liver dysfunction that can be attributed to the respiratory distress syndrome-induced hypoxia and the release of huge circulating detrimental inflammatory mediators with the ability to invade liver cells, causing hepatocyte damages and elevated liver enzymes [39]. Cardiovascular complications such as acute myocardial infarction, venous thromboembolic events, myocarditis, and heart failure may also occur in patients with COVID-19 due to direct virus invasion through ACE2, endothelial dysfunction, hypoxia, excessive inflammatory responses, oxidative stress, elevated level of angiotensin (Ag) II, and atherosclerotic plaque rupture [ 41 , 42 ]. Besides, elevated cardiac biomarkers, including troponin T, have also been demonstrated to be associated with increased inflammatory markers, suggesting that myocardial injury is linked to inflammation [43]. Gastrointestinal symptoms, such as vomiting, diarrhea, or abdominal pain, are other common clinical manifestations of COVID-19 during the early phases of the disease. Intestinal dysfunction leads to changes in intestinal microbes, thereby promoting inflammatory cytokines [ 44 ]. Consequently, ACE2 is highly expressed in the gastrointestinal tract and SARS-CoV-2 directly invades the gut tract through binding with ACE2 receptors. In this regard, ACE2 is considered a key regulator of intestinal inflammation and can enhance the risk of colitis and other gastrointestinal symptoms [45]. Clinical data have demonstrated the presence of SARS-CoV-2 particles in urine samples of patients infected with COVID-19 [ 46 ]. It has been reported that SARS-CoV-2 possesses detrimental impacts on kidney function and causes signs/symptoms of acute kidney injury [ 47 ]. The expression of ACE2 on podocytes and tubule epithelial cells makes the kidney a host candidate for SARS-CoV-2 [ 48 ]. Local inflammatory/immune reaction, direct cytotoxic viral effect, hypoxia, as well as secondary infections/sepsis induce the occurrence of endothelial dysfunction, tubular injury, and heavy proteinuria [ 49 ]. Therefore, given the involvement of host factors such as ACE and related complications attributed to oxidative stress, as well as inflammation, apoptosis, and autophagy in the complications of COVID-19, targeting them is of great importance. 4. SARS-CoV-2 Infection SARS-CoV-2 undergoes various steps of fusion, uncoating, nucleic acid synthesis, integration, protease, and assembly/release towards infection; therefore, detailed knowledge of infection pathways is critical to tackling COVID-19. It has been well-established that SARS-CoV-2 enters the host cells via two pathways, including the endocytic pathway and non-endosomal pathway, with the help of proteases (e.g., TMPRSS2); both contribute to Molecules 2021,26, 2917 4 of 32 the release of the nucleocapsid into the cytoplasm [ 22 ]. Among those factors, SARS-CoV-2 utilizes the endocytic pathway as the principal mechanism for viral entry into several types of host cells. The S protein on the surface of a coronavirus can interact with the receptor and then invade the host cells through clathrin-mediated endocytosis [ 11 ]. Recent advances have highlighted the critical role of such host receptors, including ACE2, glucose-regulated protein 78 (GRP78), cluster of differentiation 147 (CD147), and dipeptidyl peptidase (DPP4) in viral infection. 4.1. ACE2 Revealing the first phase of viral entry into the host cells, fusion/entry through facilitating co-receptors could be targeted by appropriate therapeutic agents [ 50 ]. Recent advances have highlighted the critical role of such host receptors in viral infection, including ErbB1, tyrosine kinase receptors (TKRs) [ 51 ], toll-like receptors (TLRs) [ 52 ], TNFα , ILs, interferon (IFN)- γ , and other receptors affecting the immune system [ 53 ]. The involvement of other receptors related to T cells has also been shown to play critical roles in viral infection, such as cytotoxic Tlymphocyte antigen 4 (CTLA-4), programmed death1 (PD-1), as well as T-cell immunoglobulin (Ig) and mucin domain-containing molecule 3 (TIM-3) [54,55]. Continuous uncoating and nucleic acid synthesis with the involved enzymes of RNA polymerase are other steps in virus replication, including for SARS-CoV-2. Viral chain terminase and proteases have also been shown to be promising targets against COVID-19 complications. As the final step of viral infection, the viral release could also be a hopeful target in combating COVID-19. Nowadays, host co-receptors have been considered critical agents with undeniable roles in stimulating the immune system and increasing viral infection [ 56 ]. The analysis of nucleic acid sequence within the spike proteins of SARSCoV-2 predicted the role of ACE2 in the cellular entry of the virus, which was confirmed by an in vitro study [56]. Synthesized ACE2 is folded and N-glycosylated in the endoplasmic reticulum (ER) then passes to Golgi apparatus for further modifications and packaging and is then transported to the plasma membrane [57]. Cleavage of ACE2 by A disintegrin and metalloproteinase 17 (ADAM17) leads to the release of soluble ACE2 into the extracellular environment. Consequently, angiotensin receptor I (AR I) enhances ADAM17 expression which, in turn, elevates soluble ACE2, and can therefore prevent SARS-CoV-2 entrance [ 57 , 58 ]. Additionally, in response to SARS-CoV-2, binding via clathrin-mediated endocytosis and the internalization of both the virus and its receptor, ACE2, occur [59]. The rate expression of ACE2 and its cleavage from the cell membrane contribute to the regulation of ACE2 activity [ 60 ]. It has been well-established that Ag II, which mitigates ACE2 expression, passes through type II alveolar (AT2) and type I alveolar (AT1)-extracellular-regulated kinase (ERK)/p38 mitogen-activated protein kinase (MAPK) pathway, thereby playing a pivotal role in the regulation of associated receptors [ 61 ]. Additionally, hypoxia-induced factor-1 α (HIF-1 α ) enhances the production of ACE, which, in turn, boosts the production of Ag II, and then leads to a reduced level of ACE2 [ 62 ]. SARSCoV-2-induced downregulation of ACE2 leads to an augmentation of the pro-inflammatory factor, Ag II, and causes lung injury [ 63 ]. The recognized receptor of SARS-CoV-2, ACE2, is mainly expressed in a small subset of lung cells [ 64 ]. Only minimal percentages of monocytes/macrophages in the lung expressed ACE2 [ 64 ]. It presents the possibility of direct cellular infection (with no ACE2 engagement) or the existence of other receptors involved in SARS-CoV-2 entrances [ 65 , 66 ]. In general, the critical role of the renin–angiotensin system (RAS) has been indicated in various pathological and physiological processes. Consequently, angiotensinogen is converted to Ag I by renin. Ag I is, in turn, converted to Ag II then to Ag (1–7), and Mas by ACE1 and ACE2, respectively. While Ag II binds to AR I and makes pathological outcomes, Mas binds to MasR to exert protective responses against COVID-19 [ 67 , 68 ]. Therefore, ACE2 could play the double-edged role of being a co-receptor for SARS-CoV-2 entry and generating Mas for protection [ 69 ]. As attained by COVID-19 clinical trials, susceptibility to COVID-19 infection is in a direct correlation Molecules 2021,26, 2917 5 of 32 with the activity of ACE2. Since this enzyme is enriched in the lungs, heart, brain, kidneys, intestine, testes, and placenta [ 70 – 72 ], there is a higher rate of virus presence and pathogenesis [ 73 ]. These results indicated that Ag II is likely to be the primary target of SARS-CoV-2 in the lungs [ 68 ]. Moreover, there are sex differences in the expression of ACE2. Sex hormones in males made a higher expression of ACE2 than in females, with a greater infectious rate [ 68 , 74 ]. The ACE/ACE2 activity ratio in male serum is higher than in females. Individuals with coexisting disorders, including pneumonia [ 73 ], diabetes [ 75 ], along with aging [ 74 , 76 , 77 ], cigarette use [ 78 ], pregnancy [ 71 , 79 ], hypoxia, and HIF-1 α [ 62 , 80 ], were shown to be more susceptible to the dysregulation of the ACE/ACE2 ratio. Overall, the molecular mechanisms and signaling pathways by which SARS-CoV-2 elicits its harmful effects are incompletely understood, and a few molecules have been identified as a target of SARS-CoV-2. For instance, it has been shown that SARS-CoV-2 reinforces chemokine-associated inflammation and fibrosis through IFN, with ACE2-induced Ras/Raf/mitogen-activated protein kinase kinase (MEK)/ERK/ activating protein 1 (AP1) and casein kinase (CK)2p21-activated kinase 1 (PAK1) signaling pathways [ 81 ]. It has been reported that the aforementioned pathway offers the potential for pulmonary vascular remodeling and exaggerated hypoxia [ 82 ]. Aberrant activation of PAK1 hinders immune systems and participates in the promotion of viral infection [ 83 ]. Therefore, the suppression of PAK1 or it is upstream potentially repressed SARS-CoV-2 infection. In cases of SARSCoV-2 infection, ACE2 has attracted substantial attention in COVID-19 pathogenicity [ 69 ]. Inappropriate regulation of ACE2/Ag (1–7)/Mas receptor and ACE1/Ag II type 1 receptor pathways could enhance ACE2, and thereby increase the chances of viral entry [ 69 , 84 ]. On the other hand, downregulation of ACE2 by SARS-CoV-2 infection inhibits the degradation of Ag II into Ag (1–7), exacerbates inflammation, and leads to vascular permeability and cardiovascular complications [69]. 4.2. TMPRSS2 It has been well-established that the proteolytic cleavage of the viral envelope glycoprotein by either intracellular or extracellular proteases, such as trypsin, furin, cathepsin, or transmembrane protease serine 2 (TMPRSS2), plays an important role in SARS-CoV entry [ 85 ]. Among them, TMPRSS2 has been shown to activate the spike-protein of COVID-19 for viral fusion and infectivity [ 86 ]. An accumulation of findings highlighted that the host protease TMPRSS2, employed for the entry of SARS-CoV-2 into lung epithelium, is an attractive target for pharmacologic intervention. It has been shown that pharmacologic inhibition of TMPRSS2 blocks SARS-CoV-2 entry into human lung cells. Additionally, inhibition of TMPRSS2 prevented SARS-CoV-1 infection in animal models. The TMPRSS2 gene expresses a protein of 492 amino acids which anchors to the plasma membrane. It can be divided into the catalytic chain and noncatalytic chain parts through autocatalytic cleavage between Arg255 and Ile256. After cleavage, the majority of mature proteases are membrane-bound, but their substantial portions can be released into the extracellular space [ 87 ]. It has been revealed that TMPRSS2 gene promoter possesses 15-bp androgen response element, and TMPRSS2 transcription is upregulated in the presence of androgens [ 88 ]. The activation of SARS-CoV by TMPRSS2 suppresses the blockage of SARS-CoV by IFN-induced transmembrane proteins, a class of IFN-stimulated host cell proteins that participate in inhibiting the entry of various enveloped viruses [89]. TMPRSS2 is known as a key gene in prostate cancer [ 90 ]. The hepatocyte growth factor (HGF)/c-Met cell is activated by TMPRSS2, provoking the survival pathway of HGF/c-Met receptor tyrosine kinase signaling and stimulating a pro-invasive role in prostate cancer cells. TMPRSS2 also induces inflammation by proteolytically activating the protease-activated receptor-2 (PAR-2) in the prostate. Additionally, the upregulation of PAR-2 promotes matrix metalloproteinase-2 (MMP-2) and MMP-9, both of which play a key role in the metastasis of tumor cells [89,91]. Molecules 2021,26, 2917 6 of 32 4.3. Glucose-Regulated Protein 78 (GRP78) Glucose-regulated protein 78 (GRP78), which belongs to the heat shock protein 70 family, is the master chaperone protein present in the lumen of the ER [ 92 , 93 ]. Under cell stress, overexpressed GRP78 can escape ER retention and translocate to the cell membrane [ 94 ]. Once localized in the plasma membrane, GRP78 is susceptible to virus recognition, thereby facilitating the viral entry to the host cells. It has been reported that GRP78 is a target receptor of the MERS-CoV spike protein and bat coronavirus HKU9 (bCoV-HKU9) [ 95 ]. Recently, the existence of a SARS-CoV-2 spike protein-GRP78 binding site has been predicted using the computational method [ 96 ], thus paving the route to design suitable inhibitors to prevent binding and infection. 4.4. The Cluster of Differentiation 147 (CD147) The cluster of differentiation 147 (CD147), also known as extracellular matrix metalloproteinase inducer, has recently emerged as an important receptor for SARS-CoV-2 [ 97 ]. CD147 possesses the ability to interact with various extracellular and intracellular partners which play a key role in the infection process of the human immunodeficiency virus (HIV), measles, and SARS-CoV [ 98 , 99 ]. It has been reported that CD147 can bind with multiple ligands, including cyclophilins, monocarboxylate transporters, caveolin-1, and integrins [ 100 ]. As extracellular interactive partners, cyclophilins A and B can bind to CD147 and activate it, thereby increasing the chance of infection of CD147-expressing cells [ 101 ]. It has been reported that cyclophilins A and B can interact with nsp1 of SARS-CoV [ 98 ]; however, it is yet not understood whether cyclophilins can bind to SARS-CoV-2. In an in vitro study, Wang et al. [ 102 ] revealed that meplazumab, an anti-CD147 antibody, significantly hindered the invasion of host cells by SARS-CoV-2. Surprisingly, this report has been supported by a clinical trial in which the anti-CD147 antibody inhibited SARS-CoV-2 spike protein binding and subsequently facilitated a viral clearance [ 103 ]. CD147 also participated in the regulation of nuclear factor-kappa B (NFκ B). Moreover, upregulation of CD147 leads to the activation of NFκ B which, in turn, involves inflammation and proliferative responses [ 104 ]. Additionally, cyclophilin–CD147 interaction can recruit the immune cells to the sites of inflammation via chemokine-like activity [ 105 ]. Cyclophilin 60 is identified as an important contributor protein in the expression and translocation of CD147 to the cell surface [ 106 ]. Several other proteins which bind to CD147 may affect its localization. For instance, the interaction of CD147 with the proton-coupled transporters of monocarboxylate, including MCT1 and MCT4 in the cell membrane, is highly dependent on glutamic acid residue 218 in the CD147 transmembrane domain. However, the mutation of this glutamic acid prevents the access of both CD147 and MCT to the cell membrane [ 107 ]. It has been also reported that caveolin-1 binds to CD147 on a cell surface, through which it plays a key role in the regulation of clustering and activity of CD147 [ 108 ]. As an interacting partner of CD147, integrin β 1 interacts with CD147 to regulate integrin-dependent signaling and focal adhesion kinase (FAK) activation, leading to ignition of the downstream signaling Rac/Ras/Raf/ERK and phosphoinositide 3-kinases (PI3K)/Akt pathways and an increase in the metastatic potential of hepatocellular carcinoma [ 109 ]. It has been demonstrated that CD147 increases MMPs expression through several signaling pathways, including Janus kinase (JAK)/signal transducer and activator of transcription (STAT), Ras-MEK1-MAPK, and PI3K/Akt signaling pathway [110]. 4.5. Dipeptidyl Peptidase (DPP4) Dipeptidyl peptidase (DPP4), also known as CD26, was considered as the main entry receptor for MERS-CoV [ 111 ]. The S protein of MERS-CoV specifically interacts with DPP4 receptors, thereby inducing proteolytic activation of viral entrance and viral membrane fusion with the cell membrane [ 112 ]. There is about an 80% genome sequence similarity between MERS-CoV and SARS-CoV with SARS-CoV-2. Recent evidence has shown that DPP4/CD26 can also bind to the S1 domain of the SARS-CoV-2 spike glycoprotein, indicating the potential role of DPP4/CD26 in SARS-CoV-2 adhesion/virulence [ 113 ]. The Molecules 2021,26, 2917 7 of 32 potential interaction between SARS-CoV-2 spike glycoproteins and DPP4 has been demonstrated by docking studies and needs in-depth clarification in experimental models [ 114 ]. Intriguingly, there is also evidence suggesting that DPP4 is implicated in the induction of cytokine storm, oxidative stress, the immune system, and apoptosis [ 115 ]. DPP4 has been widely studied because of its proteolytic activity on various cytokines and peptides that participate in different medical conditions [ 116 ]. In the case of proteolytic activity, DPP4 reduces incretins such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), subsequently leading to a declined insulin secretion and abnormal glucose level [ 116 ]. Additionally, DPP4 proteolysis leads to partial or total alteration in signaling and functionality of its substrates, including peptide tyrosine-tyrosine (PYY), neuropeptide Y (NPY), and stromal-derived factor 1 (e.g., SDF-1 and CXCL12) [ 117 ]. Intriguingly, there is also evidence suggesting that DPP4 is implicated in the induction of cytokine storm, activation of NFκ B pathway, oxidative stress, the immune system, and apoptosis [ 115 ]. It has been revealed that CD26/DPP4 possesses the ability to directly trigger T cell activation through CARMA1-mediated NFκ B activation in T cells which, in turn, leads to T cell proliferation and pro-inflammatory interleukin (IL)-2 cytokine production [ 118 ]. People with diabetes are at higher risk of developing the serious clinical events caused by COVID-19 because chronic hyperglycemia and inflammation contribute to an ineffective immune response [ 119 ]. In this line, DPP4 inhibitors and/or GLP-1 receptor analogs are widely used for the control of hyperglycemia in type 2 diabetes [ 120 ]. The potential role of DPP4 inhibitors in COVID-19infected patients with type 2 diabetes is not completely clarified. However, DPP4 may illustrate a potential target for decreasing the progression of the complications of type 2 diabetes in those infected with COVID-19 [ 119 ]. Therefore, DPP4 inhibition may hinder the infection and/or development of the COVID-19. 5. COVID-19: Pathogenesis, Dysregulated Pathways and Beyond Patients infected with SARS-CoV-2 exhibited various clinical manifestations such as fever, dyspnea, myalgia, and viral pneumonia [ 121 ]. In complicated patients, ARDS, acute kidney injury, cardiovascular complications, neurological side effects, and multiple organ failure have also been shown to be associated with increased mortality [ 49 , 122 , 123 ]. While the pathobiology of SARS-CoV-2 and molecular mechanisms behind the aforementioned clinical manifestations are not yet entirely known, the roles of inflammation, oxidative stress, apoptosis, and autophagy are undeniable. 5.1. Role of Inflammation in COVID-19 As previously mentioned, inflammatory pathways play important roles in the highly inflammatory conditions of pathogenesis in COVID-19 [ 124 ]. As such, in severe cases of COVID-19, patients showed higher serum levels of inflammatory cytokines, including TNFα , IL-2, IL-6, IL-7, IL-10, IFNγ , IL-1 β , IL-12, IL-18, IL-33, tumor growth factorβ (TGFβ ), macrophage inflammatory protein-1 α (MIP-1 α ), monocyte chemoattractant protein-1 (MCP-1), granulocyte-colony stimulating factor (G-CSF), interferon-inducible protein-10 (IP-10), chemokines (e.g., CXCL8, CXCL9, CXCL10, CCL2, CCL3, CCL5) [ 13 , 125 – 128 ], and c-reactive protein (CRP) [ 129 – 131 ] in the early phase as major causes of ARDS [ 132 ]. Extensive immunological responses, high levels of circulating inflammatory cytokines, substantial lymphopenia, and immune-cell infiltration are closely correlated to immunepathological changes of targeted organs [133]. In COVID-19 patients, increased neutrophils/CRP and decreased lymphocytes were revealed; this was in direct correlation with disease severity [ 13 ]. Releasing the aforementioned inflammatory factors is also called a cytokine storm, which, in turn, leads to various pathogenic complications in COVID-19 [ 134 – 136 ]. The innate immune system also employs IFN type I, IFNα and IFNβ , and IFN-stimulated response element (ISRE) as downstream mediators in exerting a critical response against viral infection, while a reduced IFN leads to rapid viral replication [ 137 , 138 ]. Consequently, IFNα / β suppresses viral dissemination/replication in the early stage of viral infection. COVID-19 Molecules 2021,26, 2917 8 of 32 employs multiple ways toward interfering with the aforementioned pathways of type I IFN production [ 127 , 139 ], including JAK-STAT/ISRE pathway phosphorylation [ 140 ]. Following the production of type I IFN, COVID-19 is equipped to suppress the inflammatory pathways [ 65 , 140 , 141 ], time-dependently [ 127 ]. Additionally, any dysregulation in the pathway leads to neutrophil/monocyte/macrophage activation and lethal pneumonia or acute respiratory distress syndrome [ 127 ]. A disturbance in the regulation of IFNs generation of pro-inflammatory cytokines produced by macrophages contributes to the apoptosis of T cells, which further hampers viral elimination [142]. During viral infection and activation of the adaptive immune response, the engagement of the T cell receptor provokes intracellular calcium overload which, in turn, induces calmodulin binding to calcineurin. Calcineurin activation participates in the nuclear factor of activated T-cell (NFAT) dephosphorylation [ 143 ]. The calcium-calcineurin-NFAT pathway boosts the generation of pro-inflammatory cytokines, thereby maintaining chronic inflammation conditions [144]. As other involved receptors, TLR-7 and TLR-3 activate the downstream signaling cascade, including NFκ B and IFN regulatory factor 3 (IRF3) [ 140 ]. Enhanced levels of pro-inflammatory cytokines and the migration of inflammatory cells into the lung tissues are the postulated mechanisms for acute lung injury. Cytokine storm disrupts tissue integrity and subsequently leads to pneumonitis [ 145 ]. Activation of various inflammatory cytokines involved in the cytokine storm is controlled by the intracellular signaling pathway JAK/STAT [ 146 ]. For instance, IL-6 which has been proven as a pivotal inflammatory cytokine, employs the JAK/STAT pathway to perform its biological functions such as immune response, inflammation, and oxidative stress. The inhibition of the IL-6/JAK/STAT pathway appears a promising therapeutic option for the alleviation of COVID-19 [147]. 5.2. Role of Oxidative Stress in COVID-19 Oxidative stress is considered a key contributor to the severity and pathogenesis of SARS-CoV-2. Over-generation of reactive oxygen species (ROS) and antioxidant depletion drive a pivotal role in viral replication and viral-related complications [ 148 , 149 ]. Some populations of innate immune cells, such as macrophages and neutrophils, would generate ROS to clear the pathogens [ 150 , 151 ]. Despite the necessity of ROS production by macrophages and monocytes for modulating immune responses and eliminating viral infection, related over-production contributes to the oxidation of cellular proteins/lipids and corrupts both infected and normal cells, thereby leading to multiple organ dysfunctions [ 152 ]. Moreover, compelling studies have shown that viral infections such a SARS-CoV are linked to the inhibition of Nrf2 and augmentation of NFκ B signaling, leading to antioxidant deprivation and inflammation [ 153 ]. Nrf2, and its downstream target antioxidant enzyme heme oxygenase-1 (HO-1), serves as a crucial signaling pathway for cytoprotection against inflammation through inhibiting critical inflammatory regulatory pathways such as NFκ B [ 148 ]. Interestingly, Nrf2-keap1/HO-1 activation accompanied by an increase in enzymatic/nonenzymatic antioxidant activities, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH), thiobarbituric acid reductase (TBARS), NAD(P)H:quinone oxidoreductase 1 (NQO-1), which, in turn, suppress oxidative mediators and lipid peroxidation, thereby alleviating the hallmarks of viral infection [ 154 , 155 ]. Therefore, the Nrf2 pathway is an auspicious therapeutic target for combating SARS-CoV pathogenesis. 5.3. Role of Apoptosis in COVID-19 Apoptosis is a determiner pathway involved in COVID-19 complications. As a pathogenic pathway, apoptosis induction in infected cells can directly lead to viral pathogenesis [ 156 ]. In SARS-CoV-infected patients, lymphopenia may occur due to T cell diminution through the activation of apoptosis [ 157 ]. Apoptosis activation mediated by human COVID-19 infection contributes to the spread of the virus [ 158 ]. Apoptosis activation is associated with numerous abnormalities in virally infected organs. In this line, SARS-CoV-2 infection stimulated apoptosis in lung epithelial/endothelial cells, which causes vascular Molecules 2021,26, 2917 9 of 32 leakage and alveolar edema, as well as acute lung injury [ 29 ]. Several mechanisms are involved in apoptosis activation by human COVID-19. It has been reported that human COVID-19 stimulates apoptosis via ER, caspase-mediated, p38MAPK, and c-Jun N-terminal kinase (JNK) dependent pathways, which are needed for viral replication [ 159 , 160 ]. From another point of view, SARS-CoV triggers apoptosis through decreasing anti-apoptotic B-cell lymphoma 2 (Bcl)-2 members (e.g., Bcl-2 and Bcl-xL) and key survival signaling pathways such as Akt. The upregulation of Akt inactivated several pro-apoptotic molecules such as glycogen synthase kinase-3 β (GSK-3 β ), caspase-9, Bad, and forkhead transcription factor Foxo1 (FKHR), thereby hampering apoptotic pathways [ 161 ]. Virus infection can trigger poly (ADP ribose) polymerase (PARP) and ultimately result in apoptosis. PARP drives an important role in programmed cell death and cytokine release [ 162 , 163 ]. Therefore, PARP inhibitors can be served as supportive treatments for alleviating the hallmarks of COVID-19. Besides, viral infections disrupt mitochondrial membrane potential and provoke pro-apoptotic factors such as cytochrome C, caspase-9, and caspase-3 [ 164 , 165 ]. Therefore, targeting particular mediators and enzymes of the apoptotic pathway is an attractive strategy for fighting a viral infection. 5.4. Role of Autophagy in COVID-19 As another critical pathway for COVID-19, autophagy is an intracellular regulated process that plays a pivotal role in the maintenance of cellular homeostasis [ 166 ]. Considering mechanistic changes in COVID-19, autophagy is a fundamental cell process in the pathogenicity of disease. This process is characterized by the formation of the double-membrane autophagosomes that subsequently fuse with acidic lysosomes to form autolysosomes through a pH-dependent mechanism. The engulfed components are then degraded with lysosomal enzymes [ 167 ]. There is increasing evidence that dysregulated autophagy seems to play an essential role in the pathogenesis of SARS-CoV, as well as its arising complications. Altered autophagy caused by viral infection is strongly associated with severe tissue damage. On the other hand, autophagy could be considered a doubleedged sword in the pathogenesis of SARS-CoV. The pro-viral or antiviral role of autophagy remains unclear [ 149 ]. The virus that enters the host cell can either be eliminated via autophagy or escape autophagic degradation and replicate in the host cell [ 168 ]. A central aspect of the pro-viral role of autophagy is to boost viral replication by the formation of double-membrane vesicles in the host cells. In fact, virus replication in the host cell begins at the ER-Golgi intermediate compartment, which is connected to autophagosome biogenesis, where the viral genome possesses a critical interaction with the proteins that are necessary to assemble a complete virus [ 169 , 170 ]. It has been identified that viral nsp6 protein was found to co-localize with the endogenous autophagy marker, LC3, suggesting a possible collaboration between autophagy and COVID-19 replication [ 168 ]. Therapeutics such as chloroquine and hydroxychloroquine elicit antiviral effects by inhibiting the fusion of autophagosomes and lysosomes, and blocks the later stages of autophagic flux [ 171 ]. On the other hand, the induction of autophagy may combat viral infection by the degradation of viral components and the augmentation of innate and adaptive immunity [ 172 ]. Induction of autophagy and inflammatory responses induced by viral infection contribute to lung injury [ 173 ]. It has been reported that the inhibition of S-phase kinase-associated protein 2 (SKP2), which is responsible for proteasomal degradation of Beclin 1, enhanced autophagy, and subsequently attenuated the replication of MERS-CoV [ 174 ]. A novel analysis has also highlighted the relation between autophagy mechanisms and antiviral/inflammatory responses in COVID-19. In this sense, PI3K/Akt/ mammalian target of rapamycin (mTOR) is a key control signaling pathway for autophagy that regulates various autophagy mediators, such as Beclin, microtuble-associated protein light chain 3 (LC3), and autophagy-related (Atg). Human COVID-19-infected hepatocytes could induce autophagy through ERK/MAPK and inhibition of the PI3K/Akt/mTOR pathway [ 175 ]. Additionally, JNK, AMP-activated protein kinase (AMPK), p38MAPK control the balance of the autophagy response to viral infection [ 176 – 178 ]. Considering the role of the afore- Molecules 2021,26, 2917 16 of 32 anti-inflammatory agents, with promising potential to combat viral infections and related complications through targeting several destructive signaling mediators [191]. Altogether, several findings revealed that phytochemicals possess the ability to suppress SARS-CoV-2 infection. Unfortunately, almost all of the current evidence focused on the efficacy of phytoactive compounds in silico and in vitro models of COVID-19, and the main antiviral mechanisms remain elusive. Therefore, the beneficial effects of phytochemical against COVID-19 and main mechanisms require in-depth research to be verified by preclinical and clinical studies. Toxicological aspects, pharmacokinetics and pharmacodynamics properties and possible side effects, and structure–activity relationship (SAR) analyses need appropriate assessment. In silico studies indicated limonin [ 280 ], berberine [ 281 ], and fisetin [ 282 ] inhibited ACE2 and spike protein [ 280 ], bound to ACE2, and increased Nrf2, HO-1, and TGFβ [ 281 ]; also led to the reduction of TNFα , IL-6, IL-1 β [ 282 ]. Other compounds such as tetrandrine, lycorine, kazinol A [ 283 ], and sinigrin [ 284 ] inhibited the early stage in HCoV-OC43infection, and also inhibited the effects against different species of CoV [ 283 ], as well as inhibited SARS-CoV 3CL pro and PL pro [ 283 , 284 ]. The results of in silico studies also demonstrated that methyl rosmarinate, calceolarioside B, myricetin 3-O-beta-D-glucopyranoside, betulinic acid, cryptotanshinone, dihomoγ -linolenic acid, kaempferol, quercetin, sugiol, licoleafol, and amaranthine may have striking potential against COVID-19 [ 285 , 286 ]. Based on in silico evidence, different flavonoids, likely tomentin A-E [ 287 ], chrysin [ 288 ], narcissin [ 289 ], cyaniding [ 290 ], and hesperetin [ 291 ], interacted with ACE2 and declined its neurological manifestation in COVID-19 [ 288 – 291 ], and also inhibited papain-like protease in COVID-19 [ 287 ]. Docking evidence indicated that baicalin binds to TMPRSS2 and leads to the inhibition of COVID-19 [ 204 ]. An in vitro study also indicated that geraniol has inhibitory effects against viral spike protein and is a useful agent for therapy against COVID-19 [ 292 ]. Additionally, other natural compounds have important roles in modulating those signaling pathways, such as malvidin, which leads to the reduction of Bax/Bcl-2, caspase-3, ILβ , and TNFα [ 50 ]. Additionally, osthole alleviated lung injury and inflammation through preventing the downregulation of ACE2 and Ang1–7 expression, thereby possessing anti-inflammatory effects [ 293 ]. Moreover, daidzein reduced TLR4, MyD88, NFκ B, MPO, IL-6, and TNFα [ 294 ], thymol reduced the level of NFκ B, IL-6, TNFα , and IL-1 β [ 295 ], hyperin reduced TNFα , IL-6, IL-1 β , and NFκ B [ 296 ], and cannabidiol declined the levels of MPO, TNFα , and IL-6 [ 297 ]. These natural products declined the level of important mediators in signaling pathways of COVID-19, and have a vital function in reducing the symptoms of COVID-19. Several phytochemicals with promising antiviral effects are presented in Table 1. Figure 1shows the proposed targets and related therapeutic candidates for SARS-CoV-2. Table 1. Candidate phytochemicals with promising antiviral effects. Phytochemical Compound Study Type Mechanism of Antiviral Activity References Alkaloid 100-hydroxyusambarensine In silico ↓RdRp [263] Berberine In vitro, In silico Antiviral effect, ↓ACE2, spike protein and increased Nrf2, HO-1 ↓TGF-β1, ROS [281] Cryptospirolepine In silico ↓RdRp [263] Emetin In vitro ↓Viral entry ↓MERS-CoV S-mediated infection, ↓SARS-CoV-2 replication [264,265] Molecules 2021,26, 2917 17 of 32 Table 1. Cont. Phytochemical Compound Study Type Mechanism of Antiviral Activity References Lycorine In vivo In vitro ↓Spread and replication of HCoV-OC43, ↓SARS-CoV-2 replication [264,266] In vitro ↓Different species of CoV [283] Oxysophoridine In vitro ↓SARS-CoV-2 replication [266,298] Strychnopentamine In silico ↓RdRp [263] Tetrandrine In vitro ↓HCoV-OC43-infected [283] Tylophorine In vitro ↓JAK2, ↓NF-κB, ↓inflammation, ↓replication [267,268] Anthocyanin Malvidin In vitro ↓Bax/Bcl-2, Caspase-3, IL-1β, TNF-α[50] Cannabinoid Cannabidiol In vitro ↓MPO, TNF-α, IL-6 [297] Coumarin Inophyllum A In silico ↓Mpro,↓replication [278] Methylgalbanate In silico ↓Mpro,↓replication [276] Osthole In vitro ↓IL-6, TNF-α, ↑ACE2 and Ang1–7 [293] Toddacoumaquinone In silico ↓Mpro,↓replication [277] Diarylheptanoid Hirsutenone In vitro ↓PLpro,↓replication [260] Flavonoid Baicalein In vitro In vivo ↓3CLpro ↓Vero E6 cells damage, ↓lesions of lung tissue, ↓replication, ↓IL-1β,↓TNF-α,↓inflammation [245,246] Biochanin A In silico ↓spike glycoprotein [247] Kaempferol In vitro In silico ↓3CLpro,↓replication [299] Luteolin In vitro In silico ↓Viral entry ↓SARS-CoV infection ↓TNF-α, IL-1β, IL-6, IL-18, NF-κB[256,300] Naringenin In vitro In silico ↓TPC2, ↓viral infection ↓TNF-α, IL-1β, IL-6, IL-18, NF-κB[251,300] Naringin In silico ↓Mpro,↓replication [249] In silico ↓Spike glycoprotein [248] Silibinin In silico ↓RdRp [255] Silymarin In silico ↓ACE2 ↓IL-6, IL-1β, TNF-α, p46-p54, p42, p38, p44, NF-κB, and JNK. [247] Taxifolin In silico ↓Mpro [253] Flavonoid Cyanidin In silico ↓ACE2 and RdRp [290] Kazinol A In vitro ↓SARS-CoV 3CLpro and PLpro [283] Narcissin In silico Bind to ACE2 [289] Tomentin A-E In silico ↓PLpro in COVID-19 [287] Flavone Baicalin In silico ↓TMPRSS2 and lead to inhibition of COVID-19 [204] Chrysin In silico ↓ACE2 and decline neurological manifestation in COVID-19 [288] Molecules 2021,26, 2917 18 of 32 Table 1. Cont. Phytochemical Compound Study Type Mechanism of Antiviral Activity References Flavonol Fisetin In vitro, In silico ↓ACE2, ↓TNF-α, IL-6, IL-1β, ↑Nrf2, GPx, SOD [282] Hesperetin In vitro ↓ ACE2 and reduce neurological sign in COVID-19 [291] Hesperetin In vitro ↓ ACE2 and reduce neurological sign in COVID-19 [291] Hyperin In vitro ↓TNF-α, IL-6, IL-1β, NF-κB [296] Isoflavone Daidzein In vitro ↓TLR4, MyD88, NF-κB, MPO, IL-6, TNF-α[294] Polyphenol Catechin In silico ↓Spike protein, ↓viral entry, ↓ACE2 [243] Curcumin In silico ↓spike protein, ↓viral entry, ↓ACE2 ↓TNF-α, IL-1β, IL-6, IL-18, NF-κB, COX-2 [242,243,301] Ellagic acid In vitro ↓Mpro,↓replication [302] Resveratrol In vitro ↓SARS-CoV-2 infection. [258,301] Sinigrin In vitro ↓SARS-CoV 3CLpro [284] Terpenoid Carvacrol In silico ↓Spike protein [292] Geraniol In vitro ↓Spike protein, ↓TNF-α, IL-1β, IL-6, iNOS, COX-2 [292] Limonin In silico ↓ACE2, 3CLpro, PLpro, RdRp and spike protein [280] Thymol In vitro ↓NF-κB, IL-6, TNF-α, IL-1β, ↑SOD [295] ACE2: angiotensin-converting enzyme 2; Bcl-2: B-cell lymphoma 2; COX-2: cyclooxygenase; ERK: extracellular-regulated kinase; GPx: glutathione peroxidase; HCoV: human coronavirus; HO-1: heme oxygenase-1; IL: interleukin; iNOS: inducible nitric oxide synthase; JAK: Janus kinase; JNK: c-Jun N-terminal kinase; M pro : main protease; MERS-CoV: Middle East respiratory syndrome coronavirus; MIP: macrophage inflammatory protein; MPO: myeloperoxidase; NFκ B: nuclear factor-kappa B; PL pro : papain-like protease; RdRp: RNA-dependent RNA polymerase; Nrf2: nuclear factor erythroid 2-related factor 2; ROS: reactive oxygen species; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SOD: superoxide dismutase; TGFβ : tumor grows factorβ ; TLRs: toll-like receptors; TNF-α: tumor necrosis factor-α; TPC2: two-pore channel 2. Molecules 2021,26, 2917 19 of 32 Molecules 2021, 26, x FOR PEER REVIEW 19 of 31 Figure 1. Multiple dysregulated pathways in COVID-19. ACE2: angiotensin-converting enzyme 2; Atg: autophagy related; Bcl-2: B-cell lymphoma 2; CAT: catalase; COX: cyclooxygenase; GST: glutathione S-transferases; HO: heme oxygenase; IFN: interferon; IKKβ: IκB kinase β; IL: interleukin; JAK: Janus kinase; LC3: light chain 3; NF-κB: nuclear factor kappa B; RdRP: RNA-dependent RNA polymerase; RTK: receptor tyrosine kinase; STAT: signal transducer and activator of transcription; TMPRSS2: transmembrane protease serine 2; TNF-α: tumor necrosis factor-α. 8. Discussion Due to the complex pathological mechanisms behind COVID-19, revealing its precise signaling pathways may open new roads for providing efficient therapies. COVID-19 employs various signaling pathways/mediators, including inflammation, oxidative stress, apoptotic, and autophagy, to overcome the immune system. It has also been shown to alter the expression of some host factors, including enzymes/mediators and co-receptors such as ACE2, as well as ILs, TNF-α, IFN-γ, Nrf2, Bax/caspases, and Beclin/LC3 to facilitate cellular infection and subsequent complications (Figure 2). Despite advances, medicinal therapy against COVID-19 remains challenging. Besides, considering the multiple mediators involved in the pathogenesis of COVID-19, and providing multi-target agents, could be a more serious step toward controlling an infection. We previously reported the conventional therapeutic agents which potentially target the inflammatory signaling pathways in COVID-19 [124]. The current review introduces candidate therapeutic targets/treatment in COVID-19, as well as the evidence of using candidate phytochemicals. In this regard, phenolic compounds, alkaloids, terpenoids, coumarins, and carotenoids Figure 1. Multiple dysregulated pathways in COVID-19. ACE2: angiotensin-converting enzyme 2; Atg: autophagy related; Bcl-2: B-cell lymphoma 2; CAT: catalase; COX: cyclooxygenase; GST: glutathione S-transferases; HO: heme oxygenase; IFN: interferon; IKK β : I κ B kinase β ; IL: interleukin; JAK: Janus kinase; LC3: light chain 3; NFκ B: nuclear factor kappa B; RdRP: RNA-dependent RNA polymerase; RTK: receptor tyrosine kinase; STAT: signal transducer and activator of transcription; TMPRSS2: transmembrane protease serine 2; TNF-α: tumor necrosis factor-α. 8. Discussion Due to the complex pathological mechanisms behind COVID-19, revealing its precise signaling pathways may open new roads for providing efficient therapies. COVID-19 employs various signaling pathways/mediators, including inflammation, oxidative stress, apoptotic, and autophagy, to overcome the immune system. It has also been shown to alter the expression of some host factors, including enzymes/mediators and co-receptors such as ACE2, as well as ILs, TNFα , IFNγ , Nrf2, Bax/caspases, and Beclin/LC3 to facilitate cellular infection and subsequent complications (Figure 2). Despite advances, medicinal therapy against COVID-19 remains challenging. Besides, considering the multiple mediators involved in the pathogenesis of COVID-19, and providing multi-target agents, could be a more serious step toward controlling an infection. We previously reported the conventional therapeutic agents which potentially target the inflammatory signaling pathways in COVID-19 [ 124 ]. The current review introduces candidate therapeutic targets/treatment in COVID-19, as well as the evidence of using candidate phytochemicals. In this regard, phenolic compounds, alkaloids, terpenoids, coumarins, and carotenoids showed potential anti-SARS-CoV-2 effects by targeting viral life cycle, virus entry/replication, spike proteins, Molecules 2021,26, 2917 20 of 32 ACE2, RdRP, PL pro , and M pro . It is worth mentioning that, despite preclinical mechanistic studies on the effects of phytochemicals on SARS-CoV-2, more clinical investigations are needed to confirm the results. More studies/methods are also needed to design a novel drug delivery system that counteracts the pharmacokinetic limitations of phytochemicals in COVID-19. Molecules 2021, 26, x FOR PEER REVIEW 20 of 31 showed potential anti-SARS-CoV-2 effects by targeting viral life cycle, virus entry/replication, spike proteins, ACE2, RdRP, PLpro, and Mpro. It is worth mentioning that, despite preclinical mechanistic studies on the effects of phytochemicals on SARS-CoV-2, more clinical investigations are needed to confirm the results. More studies/methods are also needed to design a novel drug delivery system that counteracts the pharmacokinetic limitations of phytochemicals in COVID-19. Further areas of research on novel pathophysiological signaling pathways of COVID19, especially on inflammatory, oxidative stress, apoptotic, and autophagic pathways, will show more potential candidates in the management, prevention, and treatment of COVID-19 complications. That said, more reports are still needed to confirm the benefits of targeting the aforementioned pathways in COVID-19. Figure 2. The proposed targets and related therapeutic candidates in SARS-CoV-2. Atg: autophagy-related; CAT: catalase; CQ: chloroquine; HCQ: hydroxyl chloroquine; GST-1 α: glutathione s-transferases-1α; HO-1: heme oxygenase; IFN: interferon; IL: interleukin; JAK/STAT: Janus kinase (JAK)/signal transducer and activator of transcription (STAT); LC3: light chain 3; NF-κB: nuclear factor kappa B; ROS: reactive oxygen species; RTK: receptor tyrosine kinase; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SOD: superoxide dismutase; TNF-α: tumor necrosis factor-α. Author Contributions: Conceptualization, S.F., M.H.F. and J.E.; drafting of the manuscript, S.F., Z.N., S.Z.M. and S.P.; software, S.F., reviewing and editing of the paper: S.F., Z.N., E.K.A., M.H.F., E.S.-S. and J.E.; All authors have read, revised and agreed to the published version of the manuscript. All authors have read and agreed to the published version of the manuscript. Funding: J.E. gratefully acknowledges funding from CONICYT (PAI/ACADEMIA N°79160109). Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Conflicts of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. References 1. Wang, D.; Hu, B.; Hu, C.; Zhu, F.; Liu, X.; Zhang, J.; Wang, B.; Xiang, H.; Cheng, Z.; Xiong, Y. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA 2020, 323, 1061–1069. 2. Wu, C.; Chen, X.; Cai, Y.; Zhou, X.; Xu, S.; Huang, H.; Zhang, L.; Zhou, X.; Du, C.; Zhang, Y. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern. Med. 2020, 180, 934–943. 3. Ahmed, S.F.; Quadeer, A.A.; McKay, M.R. Preliminary identification of potential vaccine targets for the COVID-19 coronavirus (SARS-CoV-2) based on SARS-CoV immunological studies. Viruses 2020, 12, 254. Figure 2. The proposed targets and related therapeutic candidates in SARS-CoV-2. Atg: autophagy-related; CAT: catalase; CQ: chloroquine; HCQ: hydroxyl chloroquine; GST-1 α : glutathione s-transferases-1 α ; HO-1: heme oxygenase; IFN: interferon; IL: interleukin; JAK/STAT: Janus kinase (JAK)/signal transducer and activator of transcription (STAT); LC3: light chain 3; NFκ B: nuclear factor kappa B; ROS: reactive oxygen species; RTK: receptor tyrosine kinase; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SOD: superoxide dismutase; TNF-α: tumor necrosis factor-α. Further areas of research on novel pathophysiological signaling pathways of COVID19, especially on inflammatory, oxidative stress, apoptotic, and autophagic pathways, will show more potential candidates in the management, prevention, and treatment of COVID-19 complications. That said, more reports are still needed to confirm the benefits of targeting the aforementioned pathways in COVID-19. Author Contributions: Conceptualization, S.F., M.H.F. and J.E.; drafting of the manuscript, S.F., Z.N., S.Z.M. and S.P.; software, S.F., reviewing and editing of the paper: S.F., Z.N., E.K.A., M.H.F., E.S.-S. and J.E.; All authors have read, revised and agreed to the published version of the manuscript. All authors have read and agreed to the published version of the manuscript. Funding: J.E. gratefully acknowledges funding from CONICYT (PAI/ACADEMIA N◦79160109). Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. 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