Cystine-knot peptides targeting cancer-relevant human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4).

Abstract	Cystine-knot peptides sharing a common fold but displaying a notably large diversity within the primary structure of flanking loops have shown great potential as scaffolds for the development of therapeutic and diagnostic agents. In this study, we demonstrated that the cystine-knot peptide MCoTI-II, a trypsin inhibitor from Momordica cochinchinensis, can be engineered to bind to cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), an inhibitory receptor expressed by T lymphocytes, that has emerged as a target for the treatment of metastatic melanoma. Directed evolution was used to convert a cystine-knot trypsin inhibitor into a CTLA-4 binder by screening a library of variants using yeast surface display. A set of cystine-knot peptides possessing dissociation constants in the micromolar range was obtained; the most potent variant was synthesized chemically. Successive conjugation with neutravidin, fusion to antibody Fc domain or the oligomerization domain of C4b binding protein resulted in oligovalent variants that possessed enhanced (up to 400-fold) dissociation constants in the nanomolar range. Our data indicate that display of multiple knottin peptides on an oligomeric scaffold protein is a valid strategy to improve their functional affinity with ramifications for applications in diagnostics and therapy.
Authors	Franziska Maaß, Joycelyn Wüstehube-Lausch, Stephan Dickgießer, Bernhard Valldorf, Michael Reinwarth, Hans-Ulrich Schmoldt, Matin Daneschdar, Olga Avrutina, Ugur Sahin, Harald Kolmar
Journal	Journal of peptide science : an official publication of the European Peptide Society (J Pept Sci) Vol. 21 Issue 8 Pg. 651-60 (Aug 2015) ISSN: 1099-1387 [Electronic] England
PMID	25964162 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright	Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.
Chemical References	CTLA-4 Antigen CTLA4 protein, human Cyclotides Peptide Library Recombinant Proteins neutravidin trypsin inhibitor MCoTI-II Avidin
Topics	Avidin (metabolism) CTLA-4 Antigen (chemistry, metabolism) Cyclotides (chemistry, genetics, pharmacology) Humans Models, Molecular Peptide Library Protein Binding Protein Engineering Recombinant Proteins (chemistry, metabolism, pharmacology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!