Structure-activity study of oncocin: On-resin guanidinylation and incorporation of homoarginine, 4-hydroxyproline or 4,4-difluoroproline residues.

Autor: Shaikh AY; Center for Peptide-Based Antibiotics, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, DK-2100, Denmark; Department of Chemistry, Khalifa University, Abu Dhabi 127788, United Arab Emirates., Björkling F; Center for Peptide-Based Antibiotics, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, DK-2100, Denmark., Zabicka D; Department of Epidemiology and Clinical Microbiology, National Medicines Institute, ul. Chełmska 30/34, 00-725 Warsaw, Poland., Tomczak M; Department of Epidemiology and Clinical Microbiology, National Medicines Institute, ul. Chełmska 30/34, 00-725 Warsaw, Poland., Urbas M; Department of Epidemiology and Clinical Microbiology, National Medicines Institute, ul. Chełmska 30/34, 00-725 Warsaw, Poland., Domraceva I; Latvian Institute of Organic Synthesis, Aizkraukles 21, 1006 Riga, Latvia., Kreicberga A; Latvian Institute of Organic Synthesis, Aizkraukles 21, 1006 Riga, Latvia., Franzyk H; Center for Peptide-Based Antibiotics, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, DK-2100, Denmark. Electronic address: henrik.franzyk@sund.ku.dk.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2023 Dec; Vol. 141, pp. 106876. Date of Electronic Publication: 2023 Sep 19.
DOI: 10.1016/j.bioorg.2023.106876
Abstrakt: Antimicrobial peptides (AMPs) often display guanidinium functionalities, and hence robust synthetic procedures are needed to facilitate access to analogues with unnatural homologues of arginine (Arg = R). Initially, a resin-bound Arg/Pro-rich fluoren-9-yl-methyloxycarbonyl-protected fragment (Fmoc-RPRPPR) of the AMP oncocin (i.e., VDKPPYLPRPRPPRRIYNR-NH 2 ) was employed in a comparative on-resin assessment of commercial guanidinylation reagents head-to-head with the recently studied bis-Boc-protected triazole-based reagent, 1H-triazole-1-[N,N'-bis(tert-butoxycarbonyl)]-carboxamidine, which was synthesized by a chromatography-free procedure. This reagent was found to enable quantitative conversion in solid-phase peptide synthesis (SPPS) of peptides displaying homoarginine (Har) residues and/or an N-terminal guanidinium group. SPPS was used to obtain analogues of the 18-mer oncocin with single as well as multiple Arg → Har modifications. In addition, the effect of replacement of proline (Pro) residues in oncocin was explored by incorporating single or multiple trans-4-hydroxy-l-proline (Hyp) or 4,4-difluoro-l-proline (Dfp) residues, which both affected hydrophobicity. The resulting peptide library was tested against both Gram-negative and Gram-positive bacteria. Analysis of the minimal inhibitory concentrations (MICs) showed that analogues, displaying modifications at positions 4, 5 and 12 (originally Pro residues), had retained or slightly improved antimicrobial activity. Next, an oncocin analogue with two stabilizing l-Arg → d-Arg replacements in the C-terminal part was further modified by triple-replacement of Pro by either Dfp or Hyp in positions 4, 5, and 12. The resulting analogue displaying three Pro → Dfp modifications proved to possess the best activity profile: MICs of 1-2 µg/mL against E. coli and Klebsiella pneumoniae, less than 1% hemolysis at 800 µg/mL, and an IC 50 above 1280 µg/mL in HepG2 cells. Thus, incorporation of bis-fluorinated Pro residues appears to constitute a novel tool in structure-activity studies aimed at optimization of Pro-rich AMPs.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that have influenced the work reported in this paper.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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