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Structural basis of substrate recognition and covalent inhibition of Cdu1 from Chlamydia trachomatis

Ramirez, Yesid and Adler, Thomas and Altmann, Eva and Klemm, Theresa and Tiesmeyer, Christian and Sauer, Florian and Sotriffer , Christoph and Kisker, Caroline (2018) Structural basis of substrate recognition and covalent inhibition of Cdu1 from Chlamydia trachomatis. ChemMedChem : chemistry enabling drug discovery, 13 (19). pp. 2014-2023. ISSN 1860-7179

Abstract

The WHO-designated neglected-disease pathogen Chlamydia trachomatis (CT) is a gram-negative bacterium responsible for the most frequently diagnosed sexually transmitted infection worldwide. CT infections can lead to infertility, blindness and reactive arthritis. CT acts as an infective agent through its ability to evade the immune response of its host, which includes the impairment of the NF-κB mediated inflammatory response and the MCL1 pro-apoptotic pathway through its deubiquitylating and deneddylating enzyme ChlaDUB1 (Cdu1). Thus Cdu1 represents an attractive therapeutic target for the treatment of CT infections. Based on the high similarity between the active sites of Cdu1 and the evolutionary related protease adenain a target-hopping approach by screening a focused set of adenain inhibitors has been pursued. This effort led to the identification of weak Cdu1 inhibitors. These cyano-pyrimidine based inhibitors represent the first active-site directed small molecule inhibitors for Cdu1. High-resolution crystal structures of Cdu1 in complex with two covalently bound cyano-pyrimidines as well as with its substrate ubiquitin have been obtained. These structural data were complemented by enzymatic assays and covalent docking studies to provide insight into Cdu1s substrate recognition, active site pocket flexibility and potential hotspots for ligand interaction. All these data provide an excellent foundation for future structure-guided medicinal chemistry optimization of this cyano-pyrimidine based scaffold towards more potent and specific Cdu1 inhibitors.

Item Type: Article
Keywords: CE proteases, covalent reversible inhibitor, DUB inhibition, target-hopping, cyano-pyrimidines
Date Deposited: 25 Oct 2018 00:45
Last Modified: 25 Oct 2018 00:45
URI: https://oak.novartis.com/id/eprint/36429

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