SARS-CoV-2 Mpro: A Potential Target for Peptidomimetics and Small-Molecule Inhibitors

Abstract

The uncontrolled spread of the COVID-19 pandemic caused by the new coronavirus SARS-CoV-2 during 2020–2021 is one of the most devastating events in the history, with remarkable impacts on the health, economic systems, and habits of the entire world population. While some effective vaccines are nowadays approved and extensively administered, the long-term efficacy and safety of this line of intervention is constantly under debate as coronaviruses rapidly mutate and several SARS-CoV-2 variants have been already identified worldwide. Then, the WHO’s main recommendations to prevent severe clinical complications by COVID-19 are still essentially based on social distancing and limitation of human interactions, therefore the identification of new target-based drugs became a priority. Several strategies have been proposed to counteract such viral infection, including the repurposing of FDA already approved for the treatment of HIV, HCV, and EBOLA, inter alia. Among the evaluated compounds, inhibitors of the main protease of the coronavirus (Mpro) are becoming more and more promising candidates. Mpro holds a pivotal role during the onset of the infection and its function is intimately related with the beginning of viral replication. The interruption of its catalytic activity could represent a relevant strategy for the development of anti-coronavirus drugs. SARS-CoV-2 Mpro is a peculiar cysteine protease of the coronavirus family, responsible for the replication and infectivity of the parasite. This review offers a detailed analysis of the repurposed drugs and the newly synthesized molecules developed to date for the treatment of COVID-19 which share the common feature of targeting SARS-CoV-2 Mpro, as well as a brief overview of the main enzymatic and cell-based assays to efficaciously screen such compounds.

A Review of the Current Landscape of SARS-CoV-2 Main Protease Inhibitors: Have We Hit the Bullseye Yet?

“…Since then, thousands of compounds have been suggested as SARS-CoV-2 M-pro inhibitors through computational methods such as protein-ligand docking, high-throughput screening experiments, computer-aided design and synthesis of new compounds. Several articles have reviewed the SARS-CoV-2 M-pro inhibitors discovered to date [ 25 , 28 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. In this review, we collected 1765 SARS-CoV-2 M-pro inhibitors from the bibliography and other sources such as the COVID Moonshot project [ 39 , 40 ] and the ChEMBL release 29 database [ 41 ].…”

2-Phenoxyacetamide derivatives as SARS-CoV-2 main protease inhibitor: In silico studies

“…During this one year, although it is still less, a series or individual peptidomimetic as well as small organic compounds have been evaluated for their inhibition against SARS-CoV-2 M pro [10] . Initial study by Stoermer had been done by designing peptidomimetic inhibitor of SARS-CoV-2 M pro through homology modeling raises an idea of utilizing peptide-based compound as this enzyme inhibitor [11] .…”

Synthesis, in silico study (DFT, ADMET) and crystal structure of novel sulfamoyloxy-oxazolidinones: Interaction with SARS-CoV-2

“…Moreover, the SARS-CoV-2 main protease is a key target for COVID-19 drug discovery. All in silico studies carried out on inhibitors which block SARS-CoV-2 replication by inhibition of main protease would be effective and specific measures for the development of new therapeutic agents against SARS-CoV-2 [21] , [22] , [23] , [24] , [25] , [26] , [27] .…”