Antimicrobial, cytotoxic and insulin‐releasing activities of the amphibian host‐defense peptide ocellatin‐3N and its L‐lysine‐substituted analogs

J. Michael Conlon, Lauren Hunter, Samir Attoub, Bruno Casciaro, Milena Mechkarska, Yasser H. A. Abdel‐Wahab

Research output: Contribution to journalArticlepeer-review

Abstract

The host-defense peptide ocellatin-3N (GIFDVLKNLAKGVITSLAS.NH ), first isolated from the Caribbean frog Leptodactylus nesiotus, inhibited growth of clinically relevant Gram-positive and Gram-negative bacteria as well as a strain of the major emerging yeast pathogen Candida parapsilosis. Increasing cationicity while maintaining amphipathicity by the substitution Asp →Lys increased potency against the microorganisms by between 4- and 16-fold (MIC ≤3 μM) compared with the naturally occurring peptide. The substitution Ala →Lys and the double substitution Asp →Lys and Ala →Lys had less effects on potency. The [D4K] analog also showed 2.5- to 4-fold greater cytotoxic potency against non-small-cell lung adenocarcinoma A549 cells, breast adenocarcinoma MDA-MB-231 cells, and colorectal adenocarcinoma HT-29 cells (LC values in the range of 12-20 μM) compared with ocellatin-3N but was less hemolytic to mouse erythrocytes. However, the peptide showed no selectivity for tumor-derived cells [LC  = 20 μM for human umbilical vein endothelial cells (HUVECs)]. Ocellatin-3N and [D4K]ocellatin-3N stimulated the release of insulin from BRIN-BD11 clonal β-cells at concentrations ≥1 nM, and [A18K]ocellatin-3N, at concentrations ≥0.1 nM. No peptide stimulated the release of lactate dehydrogenase at concentrations up to 3 μM, indicating that plasma membrane integrity had been preserved. The three peptides produced an increase in intracellular [Ca ] in BRIN-BD11 cells when incubated at a concentration of 1 μM. In view of its high insulinotropic potency and relatively low hemolytic activity, the [A18K] ocellatin analog may represent a template for the design of agents with therapeutic potential for the treatment of patients with type 2 diabetes. [Abstract copyright: © 2022 The Authors. Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd.]
Original languageEnglish
Pages (from-to)e3463
JournalJournal of Peptide Science
DOIs
Publication statusPublished online - 24 Nov 2022

Bibliographical note

Funding Information:
Funding for this study was provided by Ulster University Strategic Funding and the Northern Ireland Department of Education and Learning. The authors thank Ms. Kholoud Arafat, United Arab Emirates University, for the technical support.

Publisher Copyright:
© 2022 The Authors. Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd.

Keywords

  • Organic Chemistry
  • Drug Discovery
  • Pharmacology
  • Molecular Biology
  • Molecular Medicine
  • General Medicine
  • Biochemistry
  • Structural Biology
  • frog skin
  • Leptodactylidae
  • insulin release
  • antimicrobial peptide
  • diabetes
  • cytotoxicity

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