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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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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]
Total Authors: 6
[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
Total Affiliations: 3
Document type: Journal article
Source: PLoS One; v. 8, n. 11 NOV 29 2013.
Web of Science Citations: 10

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