Isoform-Specific Inhibition of Cyclophilins

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• 作者：Sebastian Daum ; Michael Schumann ; Sebastian Mathea ; Tobias Aumller ; Molly A. Balsley ; Stephanie L. Constant ; Boris Faux de Lacroix ; Fabian Kruska ; Manfred Braun ; Cordelia Schiene-Fischer
• 刊名：Biochemistry
• 出版年：2009
• 出版时间：July 7, 2009
• 年：2009
• 卷：48
• 期：26
• 页码：6268-6277
• 全文大小：878K
• 年卷期：v.48,no.26(July 7, 2009)
• ISSN：1520-4995

文摘

Cyclophilins belong to the enzyme class of peptidyl prolyl cis−trans isomerases which catalyze the cis−trans isomerization of prolyl bonds in peptides and proteins in different folding states. Cyclophilins have been shown to be involved in a multitude of cellular functions like cell growth, proliferation, and motility. Among the 20 human cyclophilin isoenzymes, the two most abundant members of the cyclophilin family, CypA and CypB, exhibit specific cellular functions in several inflammatory diseases, cancer development, and HCV replication. A small-molecule inhibitor on the basis of aryl 1-indanylketones has now been shown to discriminate between CypA and CypB in vitro. CypA binding of this inhibitor has been characterized by fluorescence anisotropy- and isothermal titration calorimetry-based cyclosporin competition assays. Inhibition of CypA- but not CypB-mediated chemotaxis of mouse CD4⁺ T cells by the inhibitor provided biological proof of discrimination in vivo.