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

Autor: Grosche P; Novartis Institute for Biomedical Research, Novartis Campus, CH-4002 Basel, Switzerland., Sirockin F; Novartis Institute for Biomedical Research, Novartis Campus, CH-4002 Basel, Switzerland., Mac Sweeney A; Novartis Institute for Biomedical Research, Novartis Campus, CH-4002 Basel, Switzerland., Ramage P; Novartis Institute for Biomedical Research, Novartis Campus, CH-4002 Basel, Switzerland., Erbel P; Novartis Institute for Biomedical Research, Novartis Campus, CH-4002 Basel, Switzerland., Melkko S; Novartis Institute for Biomedical Research, Novartis Campus, CH-4002 Basel, Switzerland., Bernardi A; Novartis Institute for Biomedical Research, Novartis Campus, CH-4002 Basel, Switzerland., Hughes N; Novartis Institute for Biomedical Research, Novartis Campus, CH-4002 Basel, Switzerland., Ellis D; Novartis Institute for Biomedical Research, 6201 South Freeway, Fort Worth, TX 76134-2099, United States., Combrink KD; Novartis Institute for Biomedical Research, 6201 South Freeway, Fort Worth, TX 76134-2099, United States., Jarousse N; Novartis Institute for Biomedical Research, 4560 Horton Street, Emeryville, CA 94608-2916, United States., Altmann E; Novartis Institute for Biomedical Research, Novartis Campus, CH-4002 Basel, Switzerland. Electronic address: eva.altmann@novartis.com.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2015 Feb 01; Vol. 25 (3), pp. 438-43. Date of Electronic Publication: 2014 Dec 24.
DOI: 10.1016/j.bmcl.2014.12.057
Abstrakt: Adenoviral infections are associated with a wide range of acute diseases, among which ocular viral conjunctivitis (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 treatment 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.
(Copyright © 2014 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: