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Structure-based design and optimization of potent inhibitors of the adenoviral protease

Altmann, Eva and Grosche, Philipp and Sirockin, Finton and Mac Sweeney, Aengus and Ramage, Paul and Erbel, Paulus and Melkko, Samu and Bernardi, Anna and Hughes, Nicola and Ellis, David and Jarrousse Coscoy, Nadine (2015) Structure-based design and optimization of potent inhibitors of the adenoviral protease. Structure-based design and optimization of potent inhibitors of the adenoviral protease, 25 (3). pp. 438-443. ISSN 0960-894X

Abstract

Adenoviral infections are associated with a wide range of acute diseases, among which ocular viral conjunctivits (EKC) and disseminated disease in immunocompromised patients. To date, no approved specific anti-adenoviral drug is available, but there is a growing need for an effective treament of such infections. The adenoviral protease, adenain, plays a crucial role for the viral lifecycle and thus represents an attractive therapeutic target. Structure-guided design with the objective to depeptidize tetrapeptide nitrile 1 led to the novel chemotype 2. Optimization of scaffold 2 resulted in picomolar adenain inhibitors 3a and 3b. In addition, a complementary series of irreversible vinyl sulfone containing inhibitors were rationally designed, prepared and evaluated against adenoviral protease. High resolution X-ray co-crystal structures of representatives of each series proves the successful design of these inhibitors and provides an excellent basis for future medicinal chemistry optimization of these compounds.

Item Type: Article
Keywords: Adenoviral protease inhibitor, structure-guided design, irreversible inhibitor, X-ray cocrystal structure, epidemic keratoconjunctivitis
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/24018

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