Non-Toxic Dimeric Peptides Derived from the Bothropstoxin-I Are Potent SARS-CoV-2 and Papain-like Protease Inhibitors

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; Glaucius Oliva

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 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 &gt: 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 &gt: 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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