The Influence of Short Motifs on the Anticancer Activity of HB43 Peptide

Pharmaceutics

Viviane Antonietti¹  Pascal Sonnet¹  Chiara Falciani²  Fabrizia Zevolini²  Laurent Martiny³  Hassan El Btaouri³  Claudia Herrera-León⁴  Francisco Ramos-Martín⁴  Catherine Sarazin⁴  Nicola D’Amelio⁴ 

[1] Agents Infectieux, Résistance et Chimiothérapie, AGIR UR 4294, Université de Picardie Jules Verne, UFR de Pharmacie, 80037 Amiens, France;Department of Medical Biotechnology, University of Siena, 53100 Siena, Italy;Matrice Extracellulaire et Dynamique Cellulaire UMR 7369 CNRS, Université de Reims Champagne Ardenne (URCA), 51100 Reims, France;Unité de Génie Enzymatique et Cellulaire UMR 7025 CNRS, Université de Picardie Jules Verne, 80039 Amiens, France;

关键词: anticancer;    antimicrobial;    peptides;    sequence alignment;    biomembranes;    NMR;   

DOI  :  10.3390/pharmaceutics14051089

来源: DOAJ

【 摘 要 】

Despite the remarkable similarity in amino acid composition, many anticancer peptides (ACPs) display significant differences in terms of activity. This strongly suggests that particular relative dispositions of amino acids (motifs) play a role in the interaction with their biological target, which is often the cell membrane. To better verify this hypothesis, we intentionally modify HB43, an ACP active against a wide variety of cancers. Sequence alignment of related ACPs by ADAPTABLE web server highlighted the conserved motifs that could be at the origin of the activity. In this study, we show that changing the order of amino acids in such motifs results in a significant loss of activity against colon and breast cancer cell lines. On the contrary, amino acid substitution in key motifs may reinforce or weaken the activity, even when the alteration does not perturb the amphipathicity of the helix formed by HB43 on liposomes mimicking their surface. NMR and MD simulations with different membrane models (micelles, bicelles, and vesicles) indicate that the activity reflects the insertion capability in cancer-mimicking serine-exposing membranes, supported by the insertion of N-terminal phenylalanine in the FAK motif and the anchoring to the carboxylate of phosphatidylserine by means of arginine side chains.

【 授权许可】

Unknown