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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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
Tipo de documento: Artículo
Estado:Published version
Fecha de publicación:2021
País:Brasil
Institución:UNESP
Repositorio:Repositório Institucional da UNESP
Lenguaje:Inglés
OAI Identifier:oai:repositorio.unesp.br:11449/229351
Acceso en línea:http://dx.doi.org/10.3390/molecules26164896
http://hdl.handle.net/11449/229351
Nivel de acceso:Acceso abierto
Palabra clave:COVID-19
Inhibitors
Papain-like protease
Peptides
SARS-CoV-2
Sumario: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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