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Backbone Modification in the Fungal Defensin Plectasin: beta3-Residues in the helix
Structural highlights
FunctionDEFPL_PSENR Antimicrobial peptide that potently acts against several species of Gram-positive bacteria (PubMed:16222292, PubMed:19472324). It selectively inhibits peptidoglycan biosynthesis through complex formation with the cell wall precursor lipid II (1:1 molar ratio) thus inhibiting cell wall synthesis (PubMed:20508130). It does not disrupt cell membranes (PubMed:20508130). Is especially active against numerous clinical isolates of S.pneumoniae, including all 90 different serotypes and isolates resistant to clinically used antibiotics (PubMed:16222292). In vitro, shows considerable selectivity for bacteria over mammalian cells (PubMed:16222292). The peptide synthesized in D-amino acids does not show antibacterial activity (PubMed:19472324). In vitro, acts on voltage-gated potassium channels by moderately inhibiting mammalian Kv1.3/KCNA3 (IC(50)=2.8 uM), and moderately inhibiting others potassium channels (PubMed:25568977).[1] [2] Publication Abstract from PubMedThe threat posed by bacteria resistant to common antibiotics creates an urgent need for novel antimicrobials. Non-ribosomal peptide natural products that bind Lipid II, such as vancomycin, represent a promising source for such agents. The fungal defensin plectasin is one of a family of ribosomally produced miniproteins that exert antimicrobial activity via Lipid II binding. Made up entirely of canonical amino acids, these molecules are potentially more susceptible to degradation by protease enzymes than non-ribosomal counterparts. Here, we report the development of proteomimetic variants of plectasin through the systematic incorporation of artificial backbone connectivity in the domain. An iterative secondary-structure-based design scheme yields a variant with a tertiary fold indistinguishable from the prototype defensin, potent activity against Gram positive bacteria, and low mammalian cell toxicity. Backbone modification is shown to improve oxidative folding efficiency of the disulfide-rich scaffold as well as resistance to proteolytic hydrolysis. These results broaden the scope of design strategies toward protein mimetics as well as folds and biological functions possible in such agents. Structural and Functional Mimicry of the Antimicrobial Defensin Plectasin by Analogues with Engineered Backbone Composition.,Harmon TW, Song J, Gulewicz AJ, Di YP, Horne WS Chembiochem. 2024 Dec 23:e202400951. doi: 10.1002/cbic.202400951. PMID:39714882[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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