Design of a potent antibiotic peptide based on the active region of human defensin 5

Journal of Medicinal Chemistry
Cheng WangJunping Wang

Abstract

Human defensin 5 (HD5) is a broad-spectrum antibacterial peptide with a C-terminal active region. To promote the development of this peptide into an antibiotic, we initially substituted Glu21 with Arg because it is an electronegative residue located around the active region. Although detrimental to dimer formation, the E21R substitution markedly enhanced the antibacterial activity of HD5 and increased its ability to penetrate cell membranes, demonstrating that increasing the electropositive charge compensated for the effect of dimer disruption. Subsequently, a partial Arg scanning mutagenesis was performed, and Thr7 was selected for replacement with Arg to further strengthen the antibacterial activity. The newly designed peptide, T7E21R-HD5, exhibited potent antibacterial activity, even in saline and serum solutions. In contrast to monomeric E21R-HD5, T7E21R-HD5 assembled into an atypical dimer with parallel β strands, thus expanding the role of increasing electropositive charge in bactericidal activity and providing a useful guide for further defensin-derived antibiotic design.

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Citations

Jan 10, 2017·The Journal of Physical Chemistry. B·Sang Won JungArt E Cho
May 19, 2017·FEMS Microbiology Reviews·María Eugenia Pachón-IbáñezJavier Sánchez-Céspedes
Jun 9, 2017·Biological Chemistry·Elena KudryashovaDmitri S Kudryashov
May 5, 2017·Frontiers in Microbiology·Sumathi Sankaran-WaltersChantelle Dills
Aug 31, 2019·Journal of Molecular Modeling·Sheeja V Vasudevan, Ashutosh Kumar
Aug 17, 2020·International Journal of Molecular Sciences·Surajit Bhattacharjya, Suzana K Straus
Oct 20, 2020·Frontiers in Immunology·Derry K Mercer, Deborah A O'Neil
Nov 16, 2020·Advanced Drug Delivery Reviews·Desiree SchützJanis A Müller
May 6, 2021·Biomaterials Science·Lulu WeiJianfeng Cai
May 22, 2020·Gastroenterology·Cheng WangJunping Wang
Mar 24, 2018·Journal of Medicinal Chemistry·Youhong NiuXin-Shan Ye

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