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-Cys(11), Lys(12),Lys(13)-(pBthTX-I)(2)K ((pBthTX-I)(2)K)) and derivatives against SARS-CoV-2 are reported. The lead peptide (pBthTX-I)(2)K and derivatives showed attractive inhibitory activities against SARS-CoV-2 (EC50 = 28-65 mu M) and mostly low cytotoxic effect (CC50 > 100 mu M). To shed light on the mechanism of action underlying the peptides' antiviral activity, the Main Protease (M-pro) and Papain-Like protease (PLpro) inhibitory activities of the peptides were assessed. The synthetic peptides showed PLpro inhibition potencies (IC(50)s = 1.0-3.5 mu M) and binding affinities (K-d = 0.9-7 mu M) at the low micromolar range but poor inhibitory activity against M-pro (IC50 > 10 mu M). 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.

Automated summary

This study reported on antiviral peptides and their derivatives against SARS-CoV-2, showing strong inhibitory activities with low cytotoxicity. These peptides inhibited viral enzyme activities, indicating that they are promising prototypes for the discovery and development of new drugs against SARS-CoV-2.