Generation of truncated derivatives through in silico enzymatic digest of peptide GV30 target MRSA both in vitro and in vivo

Yingxue Ma; Aifang Yao; Xiaoling Chen; Lei Wang; Chengbang Ma; Xinping Xi; Tianbao Chen; Chris Shaw; Mei Zhou

doi:10.1016/j.csbj.2021.08.039

Generation of truncated derivatives through in silico enzymatic digest of peptide GV30 target MRSA both in vitro and in vivo

Comput Struct Biotechnol J. 2021 Aug 29:19:4984-4996. doi: 10.1016/j.csbj.2021.08.039. eCollection 2021.

Authors

Yingxue Ma¹, Aifang Yao¹, Xiaoling Chen¹, Lei Wang¹, Chengbang Ma¹, Xinping Xi¹, Tianbao Chen¹, Chris Shaw¹, Mei Zhou¹

Affiliation

¹ Natural Drug Discovery Group, School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK.

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) causing serious hospital-acquired infections and skin infections has become a "superbug" in clinical treatment. Although the clinical treatment of MRSA is continuously improving, due to its unceasing global spread, MRSA has produced much heated discussion and focused study, therefore suggesting an urgent task to find new antibacterial drugs to combat this issue. Antimicrobial peptides (AMPs) are used as the last-resort drugs for treating multidrug-resistant bacterial infections, but their utilisation is still limited due to their low stability and often strong toxicity. Here, we evaluated the structure and the bioactivity of an AMP, GV30, derived from the frog skin secretions of Hylarana guentheri, and designed seven truncated derivatives based on the presence of cleavage sites for trypsin using an online proteomic bioinformatic resource PeptideCutter tool. We investigated the anti-MRSA effect, toxicity and salt- and serum-resistance of these peptides. Interestingly, the structure-activity relationship revealed that removing "Rana box" loop could significantly improve the bactericidal speed on MRSA. Among these derivatives, GV21 (GVIFNALKGVAKTVAAQLLKK-NH₂), because of its faster antibacterial effect, lower toxicity, and retains the good antibacterial activity and stability of the parent peptide, is considered to become a new potential antibacterial candidate against MRSA.

Keywords: Antibacterial effect; Antimicrobial peptides; Methicillin-resistant Staphylococcus aureus; PeptideCutter tool; Salt- and serum-resistance; Toxicity; Truncated derivatives.