Conformational analysis and cytotoxic activities of the frog skin host-defense peptide, hymenochirin-1Pa

Ilaria Serra, Mariano A. Scorciapino, Giorgia Manzo, Mariano Casu, Andrea C. Rinaldi, Samir Attoub, Milena Mechkarska, J. Michael Conlon

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Hymenochirin-1Pa (LKLSPKTKDTLKKVLKGAIKGAIAIASMA-NH2) is a host-defense peptide first isolated from skin secretions of the frog Pseudhymenochirus merlini (Pipidae). A nuclear magnetic resonance structural investigation demonstrates that the peptide has a random coil conformation in water but, in the membrane-mimetic solvent 50% (v/v) trifluoroethanol-water adopts a well-defined conformation characterized by two α-helical domains from residues K6 to G17 and from G21 to M28, with the N-terminal region unfolded. The presence of a GXXXG domain, the most common structural motif found at the interface between interacting trans-membrane helices, between residues 17 and 21, introduces a kink corresponding to a deviation from linearity of 93 ± 31°. Hymenochirin-1Pa shows broad spectrum anti-bacterial activity, including high potency against multidrug-resistant clinical isolates of Staphylococcus aureus, Acinetobacter baumannii, and Stenotrophomonas maltophilia. The peptide also shows high cytotoxic potency against human non-small lung adenocarcinoma A549 cells, breast adenocarcinoma MDA-MB-231 cells, and colorectal adenocarcinoma HT-29 cells but its therapeutic potential as an anti-cancer agent is limited by moderate hemolytic activity against human erythrocytes and lack of selectivity for tumor cells. Increasing cationicity of the peptide by substituting the Asp9residue by either l-Lys (K) or d-Lys (k) has relatively minor effects on antimicrobial and anti-tumor potencies but the [D9k] analog is non-hemolytic LC50> 400 μM. Thus, [D9k]hymenochirin-1Pa may serve as a template for the design of non-toxic antimicrobial agents for use against multidrug-resistant pathogenic bacteria.

Original languageEnglish
Pages (from-to)114-121
Number of pages8
JournalPeptides
Volume61
DOIs
Publication statusPublished (in print/issue) - Nov 2014

Bibliographical note

Publisher Copyright:
© 2014 Elsevier Inc. All rights reserved.

Keywords

  • 3D structure
  • Anticancer activity
  • Antimicrobial peptide
  • NMR

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