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.
Highlights
Prior to 2003, the only known pathogenic coronaviruses were hCoV-229E and hCoVOC43, both responsible for trivial respiratory diseases with symptoms similar to the common cold [1]
More recent results, obtained from comparative effectiveness research studies of adults hospitalized with COVID-19, instead indicated that remdesivir was associated with faster clinical improvement [69]
A series of ketone derivatives targeting SARS-CoV-2 main protease of the coronavirus (Mpro) was recently investigated by the Pfizer Inc. [102]
Summary
Prior to 2003, the only known pathogenic coronaviruses were hCoV-229E and hCoVOC43, both responsible for trivial respiratory diseases with symptoms similar to the common cold [1]. Only molecules capable of selectively inhibiting the SARS-CoV-2 Mpro activity have been effectively developed Despite their important role, the other two viral proteolytic enzymes are difficult to target due to their high degree of similarity with human proteases and the consequent drawbacks related to phenomena of non-specific inhibition. In SARS-CoV-2 Mpro , these two residues of Thr and Ile are replaced by Ala and Leu, respectively, and this maintains closer the two domains III [12,20], leading to a significant enhancement in the catalytic activity of the enzyme (3,6 fold), with a consequent increase in the catalytic turnover [30,31] This might constitute an assumption for the greater contagiousness of SARS-CoV-2 compared to its ancestor. The whole process carried out by the Mpro is depicted in Figure 4 and is divided in four phases: (1) Deprotonation of the -SH group of the Cys145 by His, with formation of the activated thiolated ion; (2) nucleophilic attack of the latter to the carbonyl carbon of the substrate and formation of a tetrahedral adduct; (3) release of the peptide hydrolysis product with the free N-terminus and regeneration of the catalytic His; (4) thioester hydrolysis with release of the remaining peptide fragment with the free C-terminus [41,42]
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