Discovery of a new class based on 6-methoxypyrimidine as efficient low weight reversible inhibitors of SARS-CoV-2 main protease (Mpro) with antiviral activity.
A low molecular weight non-peptide, heterocyclic inhibitor, that inactivates Mpro, an important enzyme for the viral cycle and its inhibition affects replication and infection propagation in SARS-CoV-2.
Abstract
The main protease Mpro of SARS-CoV-2 is an important enzyme for the viral cycle and its inhibition affects replication and infection propagation. In this way, it has been reported as an excellent target for drug design. In this work, we discovered a low molecular weight non-peptide, heterocyclic inhibitor, that inactivates Mpro. Initially, we screened a focused chemical library of heterocyclic compounds against Mpro that included several cysteine protease inhibitors. A compound based on a 6-methoxypyrimidine scaffold was identified as an inhibitor of this enzyme and structure-activity relationship studies revealed all the important groups for Mpro inhibition. Optimization of the hit compound provided a small (306 g/mol) competitive inhibitor that inactivated Mpro activity, being non-promiscuous to other cysteine proteases such as PLpro, human CatL, and cruzain. PH521 (4f) presented increased potency against SARS-CoV-2 infection of cells being 20-fold more potent than the initial hit compound.
The integrated rational design-based synthesis, biological evaluation, and computational investigations collectively identified thiadiazole/oxadiazole scaffolds as promising candidates for the development of SARS-CoV-2 inhibitors, offering valuable insights for next-generation antiviral agents targeting coronavirus pro...
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Main protease (Mpro) enzyme of Severe Acute Respiratory Syndrome Coronavirus
2 (SARS-CoV-2) cleaves polyprotein pp1a and pp1ab at 11 sites, producing essential proteins
of viral machinery, and possesses a conserved Cys145-His41 catalytic dyad. While different
mutated strains of this virus are being identified, the...
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