Resistance to Degradation and Cellular Distribution Are Important Features for the Antitumor Activity of Gomesin

Author(s)

Buri, Marcus V. ^[1] ; Domingues, Tatiana M. ^[1] ; Paredes-Gamero, Edgar J. ^{[1, 2]} ; Casaes-Rodrigues, Rafael L. ^[2] ; Rodrigues, Elaine Guadelupe ^[3] ; Miranda, Antonio ^[1]

Affiliation

^[1] Univ Fed Sao Paulo, Dept Biofis, Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Dept Bioquim, Sao Paulo - Brazil

^[3] Univ Fed Sao Paulo, Dept Microbiol Imunol & Parasitol, Sao Paulo - Brazil

• Document type: Journal article
• Source: PLoS One; v. 8, n. 11 NOV 29 2013.
• Web of Science Citations: 10

Abstract

Many reports have shown that antimicrobial peptides exhibit anticancer abilities. Gomesin (Gm) exhibits potent cytotoxic activity against cancer cells by a membrane pore formation induced after well-orchestrated intracellular mechanisms. In this report, the replacements of the Cys by Ser or Thr, and the use D-amino acids in the Gm structure were done to investigate the importance of the resistance to degradation of the molecule with its cytotoxicity. {[}Thr(2,6,11,15)]-Gm, and {[}Ser(2,6,11,15)]-Gm exhibits low cytotoxicity, and low resistance to degradation, and after 24 h are present in localized area near to the membrane. Conversely, the use of D-amino acids in the analogue {[}D-Thr(2,6,11,15)]-D-Gm confers resistance to degradation, increases its potency, and maintained this peptide spread in the cytosol similarly to what happens with Gm. Replacements of Cys by Thr and Gln by L- or D-Pro ({[}D-Thr(2,6,11,15), Pro(9)]-D-Gm, and {[}Thr(2,6,11,15), D-Pro(9)]-Gm), which induced a similar beta-hairpin conformation, also increase their resistance to degradation, and cytotoxicity, but after 24 h they are not present spread in the cytosol, exhibiting lower cytotoxicity in comparison to Gm. Additionally, chloroquine, a lysosomal enzyme inhibitor potentiated the effect of the peptides. Furthermore, the binding and internalization of peptides was determined, but a direct correlation among these factors was not observed. However, cholesterol ablation, which increase fluidity of cellular membrane, also increase cytotoxicity and internalization of peptides. beta-hairpin spatial conformation, and intracellular localization/target, and the capability of entry are important properties of gomesin cytotoxicity. (AU)

• FAPESP's process: 11/17584-0 - Studies of the structure-activity relationship and mechanism of lytic action of the antimicrobial peptide gomesin
• Grantee: Antonio de Miranda
• Support type: Regular Research Grants