2. Academic Validation
  3. Statine-based peptidomimetic compounds as inhibitors for SARS-CoV-2 main protease (SARS-CoV‑2 Mpro)

Statine-based peptidomimetic compounds as inhibitors for SARS-CoV-2 main protease (SARS-CoV‑2 Mpro)

  • Sci Rep. 2024 Apr 18;14(1):8991. doi: 10.1038/s41598-024-59442-4.
Pedro Henrique R de A Azevedo 1,  Priscila G Camargo 2,  Larissa E C Constant 3,  Stephany da S Costa 3,  Celimar Sinézia Silva 3,  Alice S Rosa 4 5,  Daniel D C Souza 4 5,  Amanda R Tucci 4 5,  Vivian N S Ferreira 4,  Thamara Kelcya F Oliveira 4 5,  Nathalia R R Borba 4,  Carlos R Rodrigues 2,  Magaly G Albuquerque 6,  Luiza R S Dias 1,  Rafael Garrett 6,  Milene D Miranda 4 5,  Diego Allonso 3 7,  Camilo Henrique da S Lima 8,  Estela Maris F Muri 9
Affiliations

Affiliations

  • 1 Laboratório de Química Medicinal, Faculdade de Farmácia, Universidade Federal Fluminense, Niterói, RJ, 24241-000, Brazil.
  • 2 Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-853, Brazil.
  • 3 Laboratório de Biotecnologia e Bioengenharia Tecidual, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-853, Brazil.
  • 4 Laboratório de Morfologia e Morfogênese Viral, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, 21040-900, Brazil.
  • 5 Programa de Pós-Graduação em Biologia Celular e Molecular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, 21040-900, Brazil.
  • 6 Programa de Pós-Graduação em Química, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-853, Brazil.
  • 7 Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-853, Brazil.
  • 8 Programa de Pós-Graduação em Química, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-853, Brazil. camilolima@iq.ufrj.br.
  • 9 Laboratório de Química Medicinal, Faculdade de Farmácia, Universidade Federal Fluminense, Niterói, RJ, 24241-000, Brazil. estelamuri@id.uff.br.
PMID: 38637583 DOI: 10.1038/s41598-024-59442-4
Abstract

COVID-19 is a multisystemic disease caused by the SARS-CoV-2 airborne virus, a member of the Coronaviridae family. It has a positive sense single-stranded RNA genome and encodes two non-structural proteins through viral cysteine-proteases processing. Blocking this step is crucial to control virus replication. In this work, we reported the synthesis of 23 statine-based peptidomimetics to determine their ability to inhibit the main Protease (Mpro) activity of SARS-CoV-2. Among the 23 peptidomimetics, 15 compounds effectively inhibited Mpro activity by 50% or more, while three compounds (7d, 8e, and 9g) exhibited maximum inhibition above 70% and IC50 < 1 µM. Compounds 7d, 8e, and 9g inhibited roughly 80% of SARS-CoV-2 replication and proved no cytotoxicity. Molecular docking simulations show putative hydrogen bond and hydrophobic interactions between specific Amino acids and these inhibitors. Molecular dynamics simulations further confirmed the stability and persisting interactions in Mpro's subsites, exhibiting favorable free energy binding (ΔGbind) values. These findings suggest the statine-based peptidomimetics as potential therapeutic agents against SARS-CoV-2 by targeting Mpro.

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