Engineered Cystine Knot Miniproteins as Potent Inhibitors of Human Mast Cell Tryptase β

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• 作者：Christian P. Sommerhoff ; Olga Avrutina ; Hans-Ulrich Schmoldt ; Dusica Gabrijelcic-Geiger ; Ulf Diederichsen ; Harald Kolmar
• 关键词：human mast cell tryptase ; protein inhibitor ; knottins ; cystine knot miniproteins ; macrocyclic peptides
• 刊名：Journal of Molecular Biology
• 出版年：2010
• 出版时间：8 January 2010
• 年：2010
• 卷：395
• 期：1
• 页码：167-175
• 全文大小：884 K

文摘

Here we report the design, chemical and recombinant synthesis, and functional properties of a series of novel inhibitors of human mast cell tryptase β, a protease of considerable interest as a therapeutic target for the treatment of allergic asthma and inflammatory disorders. These inhibitors are derived from a linear variant of the cyclic cystine knot miniprotein MCoTI-II, originally isolated from the seeds of Momordica cochinchinensis. A synthetic cyclic miniprotein that bears additional positive charge in the loop connecting the N- and C-termini inhibits all monomers of the tryptase β tetramer with an overall equilibrium dissociation constant K_i of 1 nM and thus is one of the most potent proteinaceous inhibitors of tryptase β described to date. These cystine knot miniproteins may therefore become valuable scaffolds for the design of a new generation of tryptase inhibitors.