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 , Lys ,Lys -(pBthTX-I) K ( ) and derivatives against SARS-CoV-2 are reported. The lead peptide and derivatives showed attractive inhibitory activities against SARS-CoV-2 (EC = 28-65 µM) and mostly low cytotoxic effect (CC > 100 µM). To shed light on the mechanism of action underlying the peptides' antiviral activity, the Main Protease (M ) and Papain-Like protease (PL ) inhibitory activities of the peptides were assessed. The synthetic peptides showed PL inhibition potencies (IC s = 1.0-3.5 µM) and binding affinities ( = 0.9-7 µM) at the low micromolar range but poor inhibitory activity against M (IC > 10 µM). The modeled binding mode of a representative peptide of the series indicated that the compound blocked the entry of the PL 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.