Open AccessArticle
Non-Toxic Dimeric Peptides Derived from the Bothropstoxin-I Are Potent SARS-CoV-2 and Papain-like Protease Inhibitors
by
Marjorie C. L. C. Freire, Gabriela D. Noske, Natália V. Bitencourt, Paulo R. S. Sanches, Norival A. Santos-Filho, Victor O. Gawriljuk, Eduardo P. de Souza, Victor H. R. Nogueira, Mariana O. de Godoy, Aline M. Nakamura, Rafaela S. Fernandes, Andre S. Godoy, Maria A. Juliano, Bianca M. Peres, Cecília G. Barbosa, Carolina B. Moraes, Lucio H. G. Freitas-Junior, Eduardo M. Cilli, Rafael V. C. Guido and Glaucius Oliva
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Abstract
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
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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-Cys
11, Lys
12,Lys
13-(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 (EC
50 = 28–65 µM) and mostly low cytotoxic effect (CC
50 > 100 µM). To shed light on the mechanism of action underlying the peptides’ antiviral activity, the Main Protease (M
pro) and Papain-Like protease (PL
pro) inhibitory activities of the peptides were assessed. The synthetic peptides showed PL
pro inhibition potencies (IC
50s = 1.0–3.5 µM) and binding affinities (
Kd = 0.9–7 µM) at the low micromolar range but poor inhibitory activity against M
pro (IC
50 > 10 µM). The modeled binding mode of a representative peptide of the series indicated that the compound blocked the entry of the PL
pro 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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