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Discovery and structure-based optimization of potent adenain inhibitors

Mac Sweeney, Aengus and Grosche, Philipp and Combrink, Keith and Erbel, Paulus and Hughes, Nicola and Bernardi, Anna and Ramage, Paul and Jarrousse Coscoy, Nadine and Ellis, David and Melkko, Samu and Sirockin, Finton and Altmann, Eva (2014) Discovery and structure-based optimization of potent adenain inhibitors. Discovery and structure-based optimization of potent adenain inhibitors, 5 (8). pp. 937-941. ISSN 1948-5875

Abstract

The cysteine protease adenain is the essential protease of adenovirus and as such represents a promising target for the treatment of ocular and other adenoviral infections. Through a concise two-pronged hit discovery approach we identified tetrapeptide nitrile 1 and pyrimidine nitrile 2 as complementary starting points for adenain inhibition. These hits enabled the first high resolution X-ray co-crystal structures of adenain with inhibitors bound and revealed the binding mode of 1 and 2. The screening hits were optimized by a structure-guided medicinal chemistry strategy into low nanomolar drug-like inhibitors of adenain.

Item Type: Article
Keywords: Adenoviral protease, adenoviral infection, adenain inhibitor X-ray co-crystal structure
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/21219

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