Structural analysis of caspase-1 inhibitors derived from Tethering

Acta Crystallographica. Section F, Structural Biology and Crystallization Communications
Tom O'BrienMichael J Romanowski

Abstract

Caspase-1 is a key endopeptidase responsible for the post-translational processing of the IL-1beta and IL-18 cytokines and small-molecule inhibitors that modulate the activity of this enzyme are predicted to be important therapeutic treatments for many inflammatory diseases. A fragment-assembly approach, accompanied by structural analysis, was employed to generate caspase-1 inhibitors. With the aid of Tethering with extenders (small molecules that bind to the active-site cysteine and contain a free thiol), two novel fragments that bound to the active site and made a disulfide bond with the extender were identified by mass spectrometry. Direct linking of each fragment to the extender generated submicromolar reversible inhibitors that significantly reduced secretion of IL-1beta but not IL-6 from human peripheral blood mononuclear cells. Thus, Tethering with extenders facilitated rapid identification and synthesis of caspase-1 inhibitors with cell-based activity and subsequent structural analyses provided insights into the enzyme's ability to accommodate different inhibitor-binding modes in the active site.

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Citations

Sep 13, 2012·Progress in Neurobiology·Anna Kaplan, Brent R Stockwell
Nov 7, 2006·Current Opinion in Biotechnology·Daniel A Erlanson
Sep 1, 2009·Journal of Molecular Recognition : JMR·Danzhi Huang, Amedeo Caflisch
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Nov 9, 2005·Bioorganic & Medicinal Chemistry Letters·Bruce T FahrMichael J Romanowski
Apr 13, 2018·Journal of Medicinal Chemistry·Jean-François FournierLaurent François Hennequin

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