Structure-Function Characteristics of SARS-CoV-2 Proteases and Their Potential Inhibitors from Microbial Sources

Abstract

The COVID-19 pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is considered the greatest challenge to the global health community of the century as it continues to expand. This has prompted immediate urgency to discover promising drug targets for the treatment of COVID-19. The SARS-CoV-2 viral proteases, 3-chymotrypsin-like protease (3CLpro) and papain-like cysteine protease (PLpro), have become the promising target to study due to their essential functions in spreading the virus by RNA transcription, translation, protein synthesis, processing and modification, virus replication, and infection of the host. As such, understanding of the structure and function of these two proteases is unavoidable as platforms for the development of inhibitors targeting this protein which further arrest the infection and spread of the virus. While the abundance of reports on the screening of natural compounds such as SARS-CoV-2 proteases inhibitors are available, the microorganisms-based compounds (peptides and non-peptides) remain less studied. Indeed, microorganisms-based compounds are also one of the potent antiviral candidates against COVID-19. Microbes, especially bacteria and fungi, are other resources to produce new drugs as well as nucleosides, nucleotides, and nucleic acids. Thus, we have compiled various reported literature in detail on the structures, functions of the SARS-CoV-2 proteases, and potential inhibitors from microbial sources as assistance to other researchers working with COVID-19. The compounds are also compared to HIV protease inhibitors which suggested the microorganisms-based compounds are advantageous as SARS-CoV2 proteases inhibitors. The information should serve as a platform for further development of COVID-19 drug design strategies.

In silico screening of phenylethanoid glycosides, a class of pharmacologically active compounds as natural inhibitors of SARS-CoV-2 proteases

“…In the BL2loop region of the PL pro enzyme, the residues Asn267, Tyr268 and Gln269 are found. Despite not belonging to the active site of this enzyme, interactions with the aforementioned residues indicate a factor that inhibits the catalytic activity of the protein [56] .…”

Allosteric Binding Sites of the SARS-CoV-2 Main Protease: Potential Targets for Broad-Spectrum Anti-Coronavirus Agents

“…With papain-like protease (PL pro ) cleaving two non-structural proteins at the N-terminus and main protease or 3C-Like protease (M pro or 3CL pro ) recognizing 11 separate cleavage sites at the C-terminus, this cleaving process generates 16 mature non-structural proteins. 6,[8][9][10] The remaining ORFs encode four structural proteins (spike, membrane, envelope, and nucleocapsid) and several accessory proteins. 11,12 Various important enzymes and proteins are involved in the viral replication and infectious capacity of the SARS-CoV-2 virus.…”

Natural inhibitors of SARS-CoV-2 main protease: structure based pharmacophore modeling, molecular docking and molecular dynamic simulation studies

“…Two proteases are encoded by SARS-CoV-2 RNA genome including papain-like protease (PLpro) and main protease (also known as M pro , chymotrypsin-like cysteine protease, 3C-like protease, and 3CLpro). M pro is a cysteine protease (EC 3.4.22.69) that cleaves the coronavirus polyprotein precursor at eleven conserved sites [ 18 ]. P1 for this enzyme is a Gln and P1′ is a small residue like Ser, Aln, or Gly.…”