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J Mol Biol. 2010 Jan 8;395(1):167-75. doi: 10.1016/j.jmb.2009.10.028. Epub 2009 Oct 21.

Engineered cystine knot miniproteins as potent inhibitors of human mast cell tryptase beta.

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Division of Clinical Chemistry and Clinical Biochemistry, Surgical Department, Ludwig-Maximilians-University Munich, Nussbaumstrasse 20, D-80336 Munich, Germany.


Here we report the design, chemical and recombinant synthesis, and functional properties of a series of novel inhibitors of human mast cell tryptase beta, 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 beta tetramer with an overall equilibrium dissociation constant K(i) of 1 nM and thus is one of the most potent proteinaceous inhibitors of tryptase beta described to date. These cystine knot miniproteins may therefore become valuable scaffolds for the design of a new generation of tryptase inhibitors.

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