Health and mortality-debilitating diseases caused by viruses continue to cause serious global epidemics, especially in cases where vaccines and antiviral chemotherapies are insufficient or not available. The current state of virus related pandemics is also significantly limiting drug efficacy by the emergence of drug-resistant strains. Hence, there is an urgent need to identify and develop natural product-inspired drug leads that could help control viral infections. A plethora of potentially active natural products have been isolated from fungi and screened for antiviral activity, even though none of them has reached the market yet. This entry focuses on natural products exhibiting potent activity on selected human pathogenic viruses, such as the human immunodeficiency virus (HIV), influenza virus, herpes simplex virus (HSV), hepatitis virus and other human pathogenic viruses such as enterovirus-71, and respiratory syncytial virus (RSV).

Human Immunodeficiency Virus (HIV) inhibitory natural products from fungi
A comprehensive review of the literature identifies three main targets for anti-HIV drug discovery: virus entry, reverse transcription and integration. The entry of HIV involves interactions with proteins and is a target for the discovery of new viral entry blockers. Examples of a few discoveries are provided. A bis-indolyl quinone, hinnuliquinone (25) from an unknown fungus isolated from Quercus coccifera, inhibited wildtype and clinically resistant HIV-1 protease. HIV-1 protease is a key enzyme involved in the replication and maturation of the HIV-1 virus (Singh et al. 2004). Altertoxins I–III and V, oxidized perylenes from Alternaria tenuissima, inhibited HIV-1 replication at micromolar concentrations (Bashyal et al. 2014). The dimeric tetrahydroxanthone, penicillixanthone A from Aspergillus fumigatus displayed strong anti-HIV activity by inhibiting CCR5-tropic HIV-1 SF162 and CXCR4 tropic HIV NL4-3 (Tan et al. 2017). A marine-derived A. niger produced malformin C, which exhibited a very strong anti-HIV-1 activity (Zhou et al. 2015a). An endophytic Aspergillus sp. CPCC 400735 produced three phenalone and cytochalasin derivatives also showing anti-HIV activity (Pang et al. 2017). Concentricolide from “Daldinia concentrica” (taxonomy doubtful since this species does not occur in China according to the world monograph by Stadler et al. 2014) inhibited HIV-1 by induction of cytopathic effects (Fang and Liu 2009). Novel sesquiterpenoids from Paraconiothyrium brasiliense showed moderate anti-HIV-1 replication in C8166 cells (Liu et al. 2010b). The pupukeanane sesquiterpenoid chloropupukeannolide A from Pestalotiopsis fici showed significant anti-HIV-1 activity (Liu et al. 2010c). The cytochalasan perconiasin J and the meroterpenoid periconone B from Periconia sp. displayed moderate anti-HIV activity (Liu et al. 2016, 2017b). The farnesylated isoindolinones stachybotrysams A–C and the phenylspirodrimane derivatives stachbotrysin A and G from Stachybotrys chartatum displayed moderate anti-HIV activity (Zhao et al. 2017a, b).

The three consecutive functions controlled by HIV reverse transcriptase are: RNA reverse transcription to DNA, degradation of RNA template by RNase H, and duplication of the remaining DNA strand. Inhibition of these processes is important for the discovery of anti-HIV drugs. Stachybosin D (26), a phenylspirodrimane metabolite from a sponge-derived isolate of Stachybotrys chartarum, showed inhibitory effects on HIV-1 replication by targeting reverse transcriptase. It was able to inhibit NNRTIs-resistant strains and wild-type HIV-1 (Ma et al. 2013).

Integrase is the only protein encoded by HIV-1, aside from the enzymes protease and reverse transcriptase. Singh et al. (1998, 2002a, b, 2003a, b, c) described several compounds with inhibitory activity against integrase from various fungal species. Accordingly, equisetin and phomasetin from Fusarium heterosporum and Phoma sp., respectively Singh et al. 1998); integracins (Integrastatin A (27)) from Cytonaema sp. (Singh et al. 2002a); integrastatins (from an unidentified fungus; cf. Singh et al. 2002b); epiphiobolins C and K from “Neosartorya”; i.e., Aspergillus sp.; 😯 methylanthragallol from Cylindrocarpon ianthothele; hispidin and caffeic acid from Inonotus tamaricis; 3-hydroxyterphenyllin from Aspergillus candidus (Singh et al. 2003a); naphtho-γ-pyrones from Fusarium sp. (Singh et al. 2003b); and xanthoviridicatins from Penicillium chrysogenum (Singh et al. 2003c) all showed low micromolar inhibition against the cleavage reaction of HIV integrase. Funalenone from Penicillium sp. FKI-1463 also had the same effect (Shiomi et al. 2005).

Influenza virus inhibitory natural products from fungi
The H1N1 and H3N2 viruses are among the targets of natural products of fungal origin with anti-influenza activity. The terpenoid stachyflin (28), isolated from a marine-derived isolate of Stachybotrys showed modest activity against the influenza A virus (H1N1) with an IC50 of 3 9 10−3 μM (Minagawa et al. 2002). The γ-pyrone isoasteltoxin from Aspergillus ochraceopetaliformis showed low micromolar activity (IC50 = 0.23 μM) against both influenza viruses (Wang et al. 2016). Another Aspergillus sp., strain produced the γ-pyrone derivative asteltoxin E with IC50 values of 6.2 and 3.5 μM against H1N1 and H3N2, respectively (Tian et al. 2016). 3β-Hydroxysterol from Pestalotiopsis sp. (Sun et al. 2014) and chermesinone from Nigrospora sp. (Zhang et al. 2016b) also had moderate inhibitory effects. Aureonitol, a metabolite of Gliocladium spp. inhibited influenza A and B virus replication with an EC50 of 100 nM against H3N2 via suppression of influenza hemagglutination, while significantly impairing viral adsorption (Sacramento et al. 2015).

Herpes Simplex virus (HSV) inhibitory natural products from fungi
The impotant human pathogenic viruses HSV-1 and HSV-2 were also subject of sceening programs of fungal metabolite libraries, even though up to date no drug could be discovered that would match the activity of the market standard. Coccoquinone, an anthraquinone from Aspergillus versicolor, demonstrated an IC50 of 3 μM against HSV-1 (Huang et al. 2017a, b). Five lipopeptides from the marine-derived fungus Scytalidium sp. showed moderate anti-HSV-1 and anti-HSV-2 activities in a dose- and time dependent pattern (Rowley et al. 2003). The diphenyl ether glycoside cordyol C from Cordyceps sp. BCC 186 exhibited significant anti-HSV-1 activity with an IC50 value of 1.3 μg/ml (Bunyapaiboonsri et al. 2011). Hepatitis virus inhibitory natural products from fungi One novel tricyclic polyketide derived from a collection of fungal-derived compounds, vanitaracin A (29), was reported to inhibit viral entry process with an IC50 value of 0.6 μM and good selectivity. It was observed to directly interact with the HBV entry receptor correlated to hepatitis D virus and impaired viral bile acid transport pathway. This compound also inhibited all HBV genotypes (A–D) (Kaneko et al. 2015). The anthraquinone metabolite, 2′R-1-hydroxyisorhodoptilonmetrin, showed better anti-hepatitis B virus activity as compared to the positive drug control, lamivudine (Jin et al. 2018). The epipolythiodioxopiperazine derivative, 11′-deoxyverticillin A, showed antiviral activity by decreasing HBV-X replication through inhibition of Akt activity or depletion of the autophagic genes, LC3 and p62 (Wu et al. 2015a). Sandargo et al. (2018) and Narmani et al. (2019) have recently discovered additional anti-HCV agents like 4-hydroxypleurogrisein (30) from the nematode trapping basidiomycete Hohenbuehelia grisea and cytosporaquinone B (31) from an Iranian phytopathogen belonging to the genus Cytospora. Recently Sandargo et al.(2019b) reported the meroterpenoid rhodatin (32) from cultures of the rare basidiomycete Rhodotus palmatus and also found significant anti-HCV activities for this compound, which features a new carbon skeleton.

In view of the fact that newly arising viral diseases are steadily being reported and they can spread more easily due to gflobalization effects, the search for novel antiviral agents is as of recently gaining importance. Some of the natural products pointed out in this entry may potentially find their way to antiviral drug development in the future. However, the discovery of new chemical derivatives with nanomolar activity and high selectivity indices is still warranted.