Non-toxic dimeric peptides derived from the bothropstoxin-I are potent SARS-CoV-2 and papain-like protease inhibitors

The COVID-19 outbreak has rapidly spread on a global scale, affecting the economy and public health systems throughout the world. In recent years, peptide-based therapeutics have been widely studied and developed to treat infectious diseases, including viral infections. Herein, the antiviral effects...

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Detalhes bibliográficos
Autores: Freire, Marjorie C. L. C., Noske, Gabriela D., Bitencourt, Natália V. [UNESP], Sanches, Paulo R. S. [UNESP], Santos-Filho, Norival A. [UNESP], Gawriljuk, Victor O., de Souza, Eduardo P., Nogueira, Victor H. R., de Godoy, Mariana O., Nakamura, Aline M., Fernandes, Rafaela S., Godoy, Andre S., Juliano, Maria A., Peres, Bianca M., Barbosa, Cecília G., Moraes, Carolina B., Freitas-Junior, Lucio H. G., Cilli, Eduardo M. [UNESP], Guido, Rafael V. C., Oliva, Glaucius
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:Brasil
Recursos:Universidade Estadual Paulista (UNESP)
Repositorio:Repositório Institucional da UNESP
Idioma:inglés
OAI Identifier:oai:repositorio.unesp.br:11449/229351
Acesso em linha:http://dx.doi.org/10.3390/molecules26164896
http://hdl.handle.net/11449/229351
Access Level:acceso abierto
Palavra-chave:COVID-19
Inhibitors
Papain-like protease
Peptides
SARS-CoV-2
Descrição
Resumo:The COVID-19 outbreak has rapidly spread on a global scale, affecting the economy and public health systems throughout the world. In recent years, peptide-based therapeutics have been widely studied and developed to treat infectious diseases, including viral infections. Herein, the antiviral effects of the lysine linked dimer des-Cys11, Lys12,Lys13-(pBthTX-I)2K ((pBthTX-I)2K)) and derivatives against SARS-CoV-2 are reported. The lead peptide (pBthTX-I)2K and derivatives showed attractive inhibitory activities against SARS-CoV-2 (EC50 = 28–65 µM) and mostly low cytotoxic effect (CC50 > 100 µM). To shed light on the mechanism of action underlying the peptides’ antiviral activity, the Main Protease (Mpro) and Papain-Like protease (PLpro) inhibitory activities of the peptides were assessed. The synthetic peptides showed PLpro inhibition potencies (IC50s = 1.0–3.5 µM) and binding affinities (Kd = 0.9–7 µM) at the low micromolar range but poor inhibitory activity against Mpro (IC50 > 10 µM). The modeled binding mode of a representative peptide of the series indicated that the compound blocked the entry of the PLpro substrate toward the protease catalytic cleft. Our findings indicated that non-toxic dimeric peptides derived from the Bothropstoxin-I have attractive cellular and enzymatic inhibitory activities, thereby suggesting that they are promising prototypes for the discovery and development of new drugs against SARS-CoV-2 infection.

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