Altmann, Eva, Grosche, Philipp, Sirockin, Finton, Mac Sweeney, Aengus, Ramage, Paul, Erbel, Paulus, Melkko, Samu, Bernardi, Anna, Hughes, Nicola, 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