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Development of Therapeutic Gramicidin S Analogues Bearing Plastic β,γ‐Diamino Acids
Author(s) -
Guan Qinkun,
Chen Kaisen,
Chen Qiang,
Hu Jianguo,
Cheng Keguang,
Hu Chengfei,
Zhu Jibao,
Jin Yi,
Miclet Emeric,
Alezra Valérie,
Wan Yang
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000097
Subject(s) - gramicidin s , gramicidin , antimicrobial , chemistry , antibacterial activity , antimicrobial peptides , bacteria , peptide , therapeutic index , structure–activity relationship , biological activity , biochemistry , membrane , stereochemistry , biology , pharmacology , in vitro , drug , organic chemistry , genetics
Gramicidin S (GS), one of the most widely investigated antimicrobial peptides (AMPs), is known for its robust antimicrobial activity. However, it is restricted to topical application due to undesired hemolytic activity. With the aim of obtaining nontoxic GS analogues, we describe herein a molecular approach in which the native GS β‐turn region is replaced by synthetic β,γ‐diamino acids (β,γ‐DiAAs). Four β,γ‐DiAA diastereomers were employed to mimic the β‐turn structure to afford GS analogues GS 3 – 6 , which exhibit diminished hemolytic activity. A comparative structural study demonstrates that the (β R ,γ S )‐DiAA is the most‐stable β‐turn mimic. To further improve the therapeutic index (e. g., high antibacterial activity and low hemolytic activity) and to extend the molecular diversity, GS 5 and GS 6 were used as structural scaffolds to introduce additional hydrophobic or hydrophilic groups. We show that GS 6K , GS 6F and GS display comparable antibacterial activity, and GS 6K and GS 6F have significantly decreased toxicity. Moreover, antibacterial mechanism studies suggest that GS 6K kills bacteria mainly through the disruption of the membrane.