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

Abstract

Recent studies have shown that the peptide [des-Cys11,Lys12,Lys13-(p-BthTX-I)2K] (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.

Development of New Leishmanicidal Compounds via Bioconjugation of Antimicrobial Peptides and Antileishmanial Guanidines

“…Similarly, this peptide demonstrated no toxicity against peritoneal macrophages. These findings align with those of Bitencourt et al, 42 who reported minimal hemolytic activity, below 5%, even at a 1 μM) than that of GVL1 alone. For the amastigote form, the IC 50 of (GVL1)-p-Bt was eight times lower than that of guanidine alone.…”

“…Similarly, this peptide demonstrated no toxicity against peritoneal macrophages. These findings align with those of Bitencourt et al, who reported minimal hemolytic activity, below 5%, even at a concentration of 512 μg mL –1 , suggesting the nontoxic nature of p-Bt. The introduction of guanidine to p-Bt enhanced the antipromastigote activity of GVL1.…”

“…This peptide that lacks a well-defined structure or membranolytic action mechanism 41 was not cytotoxic. Enzymatic inhibition underlies its antiviral activity, 42 also demonstrating its ability to penetrate the cell. This peptide could traverse the parasite membrane and transport the guanidine into the parasite, thereby enhancing the biological activity.…”

The Dimeric Peptide (KKYRYHLKPF)2K Shows Broad-Spectrum Antiviral Activity by Inhibiting Different Steps of Chikungunya and Zika Virus Infection

“…Peptides exhibit characteristics that favor their use in therapeutic approaches, such as cellular biocompatibility and low toxicity [ 18 , 19 , 20 ]. The peptide (p-BthTX-I) 2 K is a synthetic peptide with a structure based on another peptide [(p-BthTX-I) 2 ] derived from the BthTX-I toxin in snake venom, which had previously demonstrated activity against several Gram-positive and Gram-negative bacteria [ 23 , 38 ] and antiviral activity against SARS-CoV-2 [ 24 ], which is an enveloped positive-sense single-stranded RNA virus similar to ZIKV and CHIKV. In this study, we assessed the antiviral activity of the (p-BthTX-I) 2 K peptide against CHIKV and ZIKV infection, as well as the steps in the viral replicative cycle in which this peptide shows activity.…”