Synthetic Flavonoid Analogues as CatB/CatL Inhibitors with Potential Anti-SARS-CoV-2 Activity
5 affiliations
- 1Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais , , Av. Antônio Carlos, 6627, Pampulha , , ,
- 2Instituto de Química, Universidade Federal de Mato Grosso do Sul , , Avenida Senador Filinto Müller, 1555 Cidade Universitária , , ,
- 3University of Mogi das Cruzes (UMC) , , Av. Dr. Cândido Xavier de Almeida Souza, 200, Centro Cívico , , ,
- 4Universidade Federal de Minas Gerais , , Av. Antônio Carlos, 6627, Pampulha , , ,
- 5Universidade de São Paulo (USP) , , Av. Trabalhador São-Carlense, 400 , , ,
Abstract
The COVID-19 pandemic profoundly affected global public health. Intensive efforts have led to the development of vaccines and antiviral drugs. However, the emergence of SARS-CoV-2 variants has raised concerns about resistance to therapies, making the exploration of alternative molecular pathways a promising strategy. Cathepsins stand out in this context due to their crucial role in mediating SARS-CoV-2 entry via endosomes. Structurally, these enzymes share high similarity with proteases from other organisms such as Leishmania CPB. Previously, we reported the synthesis and activity of 17 flavonoid derivatives as CPB inhibitors with robust antimicrobial activity. Motivated by the high resemblance between the active sites of CPB and CatB, we evaluated the anti-SARS-CoV-2 activity of these compounds and validated cathepsins as their main molecular target. Among them, nine flavonoid derivatives exhibited potent simple-linear noncompetitive dual CatB/CatL inhibition, with Ki values ranging from 3.20 to 29.05 μM for CatB and from 2.41 to 12.44 μM for CatL. Chalcones 1c, 2a, and 2b translated this enzymatic activity into significant reductions in SARS-CoV-2 titers (IC50 = 12.06, 1.05, and 2.12 μM, respectively), while demonstrating low toxicity in both Vero-CCL81 and L929 cells. Their potential direct effects on viral replication were also evaluated using SARS-CoV-2 main protease assays and virucidal tests. No compound showed activity on viral targets, suggesting that cathepsin inhibition is their potential antiviral mechanism. Although additional mechanistic assays are still required, these data provide initial support for the involvement of dual CatB/CatL as antiviral targets and offer insights for the development of chalcone-based leads against COVID-19.
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BibTeX
@article{lourenco2026synthetic,
title = {{Synthetic Flavonoid Analogues as CatB/CatL Inhibitors with Potential Anti-SARS-CoV-2 Activity}},
author = {Estela M. G. Lourenço and Marli de F. C. Emiliano and Silvana Ribeiro and Felipe A. Clarindo and Luan D. S. Vianna and Thaís de F. S. Moraes and Erik V. de S. Reis and Aline A. de Souza and Luiza V. Barreto and Mauricio F. M. Machado and Adilson Beatriz and Letícia G. de Pontes and Mariana O. de Godoy and Glaucius Oliva and Rafael V. C. Guido and Jordana G. A. Coelho-dos-Reis and Wagner A. de S. Judice and Dênis P. de Lima and Rafaela S. Ferreira},
journal = {ACS Omega},
year = {2026},
month = oct,
doi = {10.1021/acsomega.6c07800},
url = {https://pubs.acs.org/acsodf/article/11/41/63677/5445576/Synthetic-Flavonoid-Analogues-as-CatB-CatL},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Synthetic Flavonoid Analogues as CatB/CatL Inhibitors with Potential Anti-SARS-CoV-2 Activity
AU - Estela M. G. Lourenço
AU - Marli de F. C. Emiliano
AU - Silvana Ribeiro
AU - Felipe A. Clarindo
AU - Luan D. S. Vianna
AU - Thaís de F. S. Moraes
AU - Erik V. de S. Reis
AU - Aline A. de Souza
AU - Luiza V. Barreto
AU - Mauricio F. M. Machado
AU - Adilson Beatriz
AU - Letícia G. de Pontes
AU - Mariana O. de Godoy
AU - Glaucius Oliva
AU - Rafael V. C. Guido
AU - Jordana G. A. Coelho-dos-Reis
AU - Wagner A. de S. Judice
AU - Dênis P. de Lima
AU - Rafaela S. Ferreira
PY - 2026
DA - 2026/10/06
JO - ACS Omega
DO - 10.1021/acsomega.6c07800
UR - https://pubs.acs.org/acsodf/article/11/41/63677/5445576/Synthetic-Flavonoid-Analogues-as-CatB-CatL
AB - The COVID-19 pandemic profoundly affected global public health. Intensive efforts have led to the development of vaccines and antiviral drugs. However, the emergence of SARS-CoV-2 variants has raised concerns about resistance to therapies, making the exploration of alternative molecular pathways a promising strategy. Cathepsins stand out in this context due to their crucial role in mediating SARS-CoV-2 entry via endosomes. Structurally, these enzymes share high similarity with proteases from other organisms such as Leishmania CPB. Previously, we reported the synthesis and activity of 17 flavonoid derivatives as CPB inhibitors with robust antimicrobial activity. Motivated by the high resemblance between the active sites of CPB and CatB, we evaluated the anti-SARS-CoV-2 activity of these compounds and validated cathepsins as their main molecular target. Among them, nine flavonoid derivatives exhibited potent simple-linear noncompetitive dual CatB/CatL inhibition, with Ki values ranging from 3.20 to 29.05 μM for CatB and from 2.41 to 12.44 μM for CatL. Chalcones 1c, 2a, and 2b translated this enzymatic activity into significant reductions in SARS-CoV-2 titers (IC50 = 12.06, 1.05, and 2.12 μM, respectively), while demonstrating low toxicity in both Vero-CCL81 and L929 cells. Their potential direct effects on viral replication were also evaluated using SARS-CoV-2 main protease assays and virucidal tests. No compound showed activity on viral targets, suggesting that cathepsin inhibition is their potential antiviral mechanism. Although additional mechanistic assays are still required, these data provide initial support for the involvement of dual CatB/CatL as antiviral targets and offer insights for the development of chalcone-based leads against COVID-19.
SN - 2470-1343
ER -