Effects of Dimerization, Dendrimerization, and Chirality in p-BthTX-I Peptide Analogs on the Antibacterial Activity and Enzymatic Inhibition of the SARS-CoV-2 PLpro Protein

Recent studies have shown that the peptide [des-Cys(11),Lys(12),Lys(13)-(p-BthTX-I)(2)K] (p-Bth) is a p-BthTX-I analog that shows enhanced antimicrobial activity, stability and hemolytic activity, and is easy to obtain compared to the wild-type sequence. This molecule also inhibits SARS-CoV-2 viral infection in Vero cells, acting on SARS-CoV-2 PLpro enzymatic activity. Thus, the present study aimed to assess the effects of structural modifications to p-Bth, such as dimerization, dendrimerization and chirality, on the antibacterial activity and inhibitory properties of PLpro. The results showed that the dimerization or dendrimerization of p-Bth was essential for antibacterial activity, as the monomeric structure led to a total loss of, or significant reduction in, bacterial activities. The dimers and tetramers obtained using branched lysine proved to be prominent compounds with antibacterial activity against Gram-positive and Gram-negative bacteria. In addition, hemolysis rates were below 10% at the corresponding concentrations. Conversely, the inhibitory activity of the PLpro of SARS-CoV-2 was similar in the monomeric, dimeric and tetrameric forms of p-Bth. Our findings indicate the importance of the dimerization and dendrimerization of this important class of antimicrobial peptides, which shows great potential for antimicrobial and antiviral drug-discovery campaigns.

Automated summary

Recent studies have found that the peptide [des-Cys(11),Lys(12),Lys(13)-(p-BthTX-I)(2)K] (p-Bth) is a potent analog with enhanced antimicrobial activity and inhibitory effects against SARS-CoV-2. The dimerization and dendrimerization of p-Bth are crucial for its antibacterial activity, while the inhibitory activity against PLpro remains consistent regardless of the structure. These findings highlight the importance of dimerization and dendrimerization in the development of antimicrobial peptides.