Potent and selective inhibitory effect of 4-aminoquinoline derivatives on SARS-CoV-2 replication

Innovative Medicines & Omics2024Vol. 1(1), pp. 3442–3442

Nícolas Glanzmann, Thamara Kelcya Fonseca Oliveira, Vinícius Carius de Souza, Amanda Resende Tucci, Eduarda Alves Penna, Alice Santos Rosa, Maria Luiza Pereira Baltazar, Matheus José Novais Landim, Vivian Neuza S. Ferreira, Pamella Constantino-Teles, Daniel Dias Countinho Souza, Sylvia Roxo, Caroline S. de Freitas, Aline de Paula Dias da Silva, Thiago Moreno L. Souza, Priscila Vanessa S. Zabala Capriles, Milene Dias Miranda, Adilson David da Silva

Abstract

The global coronavirus disease 2019 (COVID-19) pandemic, caused by the highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), had resulted in significant mortality worldwide. In 2020, the World Health Organization started the solidarity clinical trial to assess the efficacy of four proposed therapeutic strategies, including chloroquine (CQ), a 4-aminoquinoline molecule. However, CQ lacks clinical benefit and, therefore, failed to show in vitro anti-SARS-CoV-2 activity in TMPRSS2-expressing cells, such as Calu-3 cell line, which recapitulate human type II pneumocytes. Nevertheless, other 4-aminoquinoline derivatives have shown high affinity toward the SARS-CoV-2 main protease (Mpro). This study aimed to evaluate, in vitro and in silico, the inhibitory potential of nine 4-aminoquinoline derivatives against SARS-CoV-2, building upon the observed antiviral activity of established antimalarial drugs. We assessed the ability of these derivatives to inhibit SARS-CoV-2 (wild type and Omicron variant) replication in Vero E6 and Calu-3 cell lines. In addition, we conducted docking studies to determine the binding affinity and protein-ligand interactions. Notably, these derivatives exhibited potent antiviral activity with low cytotoxicity in Vero E6 and Calu-3 cell models. In silico investigations targeting the Mpro enzyme supported the potential of the derivatives as promising agents in the fight against SARS-CoV-2. Our findings underscore the potential of these 4-aminoquinoline derivatives as robust inhibitors of SARS-CoV-2 and advocate for further research to explore their therapeutic applications, providing valuable insights for future drug development strategies.

Abstract

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