Antiviral fungal metabolites and some insights into their contribution to the current COVID-19 pandemic

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak, which started in late 2019, drove the scientific community to conduct innovative research to contain the spread of the pandemic and to care for those already affected. Since then, the search for new drugs that are effective against the virus has been strengthened. Featuring a relatively low cost of production under well-defined methods of cultivation, fungi have been providing a diversity of antiviral metabolites with unprecedented chemical structures. In this review, we present viral RNA infections highlighting SARS-CoV-2 morphogenesis and the infectious cycle, the targets of known antiviral drugs, and current developments in this area such as drug repurposing. We also explored the metabolic adaptability of fungi during fermentation to produce metabolites active against RNA viruses, along with their chemical structures, and mechanisms of action. Finally, the state of the art of research on SARS-CoV-2 inhibitors of fungal origin is reported, highlighting the metabolites selected by docking studies.

Keywords: Antiviral compounds; Drug discovery; Fungi secondary metabolites; Molecular docking; SARS-CoV-2.

Graphical abstract

Fig. 1

Emergence and reemergence of viral diseases worldwide.

Fig. 2

Chemical structures of verrucarins A (1) and J (2), trichothecenes with antiviral potential, highlighting structural features related to toxicity.

Fig. 3

Structures of diketopiperazines 3, 4, and 5, with reference to their classification and features related to toxicity (sulfur bridges).

Fig. 4

Schematic representation of Coronaviridae viral particle structure. The SARS-CoV-2 surface proteins (spike, envelope (E), membrane (M), nucleocapsid, hemagglutinin), and the (+) sense single-strand helicoidal RNA are represented.

Fig. 5

SARS-CoV-2 reproduction cycle. The schematic cycle of enveloped betacoronavirus divided into four main infection phases. (1) Attachment and entry: viral recognition of the ACE2 host-cell receptor proceeds by spike protein cleavage (S1/S2) for cell invasion engagement. (2) Genome uncoating: after cell fusion or endosomal penetration, the viral genome is released in the host-cytoplasm with nucleocapsid untied. (3) RNA replication and protein production: the main phase in the viral invasion is the use of the host-cell apparatus for virion particle reproduction. The RNA genome is replicated for new particle assembly and translated for viral-protein production including autocatalytic proteases (M^pro and PL^pro), composing an arsenal of 16 non-structural proteins for replicase assemble. (4) Final process: reorganization of the envelope membrane and the newly synthesized proteins and genome for virion particle release via exocytosis. Some compounds that inhibit viral reproduction are indicated.

Fig. 6

SARS-CoV-2 Main Protease 3D structure. M^pro functional protein is organized on a homodimer. Each monomer includes three different functional domains (DI, DII, and DII). The catalytic cleft is between DI and DII with a His41 and C145 catalytic dyad. DIII is involved in homodimer stabilization. A285 residues differ from SARS-CoV M^pro homolog and contribute to protease activity improvement. Reference protein model PDB 6Y2E.

Fig. 7

Chemical structures of some current antiviral drugs and their targets. (A) 6–8: maraviroc, bepridil and sertraline acting as entry/fusion inhibitors; (B) 9–11: amantadine, bicyclan JM2763 and hypericin as viral uncoating inhibitors; (C) 12–13: nevirapine and efavirenz as non-nucleoside reverse transcriptase inhibitors; (D) 14–16: ritonavir, lopinavir and saquinavir as integrase inhibitors; (E) 17–18: remdesivir and ribavirin nucleoside analogs which target the viral RNA polymerase; (F) 19: oseltamivir as a neuraminidase inhibitor.

Fig. 8

Chemical structures of fungal metabolites (20–36) reported as antiviral agents.

Fig. 9

Chemical structures of antiviral fungal metabolites 37–53.

Fig. 10

Chemical structures of antiviral fungal metabolites 54–64.

Fig. 11

Chemical structures of fungal metabolites 65–83 with potential SARS-CoV-2 antiviral effect.

Fig. 12

Clinical trials with quercetin (82) or with its 3-O-glucoside (83), recorded on WHO ICTRP and ClinicalTrials.gov (July 2021).