Redesigned Spider Peptide with Improved Antimicrobial and Anticancer Properties

Gomesin, a disulfide-rich antimicrobial peptide produced by the Brazilian spider Acanthoscurria gomesiana, has been shown to be potent against Gram-negative bacteria and to possess selective anticancer properties against melanoma cells. In a recent study, a backbone cyclized analogue of gomesin was...

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Bibliographic Details
Published in:	ACS chemical biology Vol. 12; no. 9; pp. 2324 - 2334
Main Authors:	Troeira Henriques, Sónia, Lawrence, Nicole, Chaousis, Stephanie, Ravipati, Anjaneya S, Cheneval, Olivier, Benfield, Aurélie H, Elliott, Alysha G, Kavanagh, Angela Maria, Cooper, Matthew A, Chan, Lai Yue, Huang, Yen-Hua, Craik, David J
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 15-09-2017
Subjects:	Animals Anti-Infective Agents - chemistry Anti-Infective Agents - pharmacology Antimicrobial Cationic Peptides - chemistry Antimicrobial Cationic Peptides - pharmacology Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Bacteria - drug effects Bacterial Infections - drug therapy Cell Line, Tumor Cell Survival - drug effects Fungi - drug effects Humans Leukemia - drug therapy Lipid Bilayers - metabolism Melanoma - drug therapy Mycoses - drug therapy Spiders - chemistry
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Summary:	Gomesin, a disulfide-rich antimicrobial peptide produced by the Brazilian spider Acanthoscurria gomesiana, has been shown to be potent against Gram-negative bacteria and to possess selective anticancer properties against melanoma cells. In a recent study, a backbone cyclized analogue of gomesin was shown to be as active but more stable than its native form. In the current study, we were interested in improving the antimicrobial properties of the cyclic gomesin, understanding its selectivity toward melanoma cells and elucidating its antimicrobial and anticancer mode of action. Rationally designed analogues of cyclic gomesin were examined for their antimicrobial potency, selectivity toward cancer cells, membrane-binding affinity, and ability to disrupt cell and model membranes. We improved the activity of cyclic gomesin by ∼10-fold against tested Gram-negative and Gram-positive bacteria without increasing toxicity to human red blood cells. In addition, we showed that gomesin and its analogues are more toxic toward melanoma and leukemia cells than toward red blood cells and act by selectively targeting and disrupting cancer cell membranes. Preference toward some cancer types is likely dependent on their different cell membrane properties. Our findings highlight the potential of peptides as antimicrobial and anticancer leads and the importance of selectively targeting cancer cell membranes for drug development.
ISSN:	1554-8929 1554-8937
DOI:	10.1021/acschembio.7b00459