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Bioorg Med Chem Lett. 2015 Feb 1;25(3):438-43. doi: 10.1016/j.bmcl.2014.12.057. Epub 2014 Dec 24.

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

Author information

1
Novartis Institute for Biomedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
2
Novartis Institute for Biomedical Research, 6201 South Freeway, Fort Worth, TX 76134-2099, United States.
3
Novartis Institute for Biomedical Research, 4560 Horton Street, Emeryville, CA 94608-2916, United States.
4
Novartis Institute for Biomedical Research, Novartis Campus, CH-4002 Basel, Switzerland. Electronic address: eva.altmann@novartis.com.

Abstract

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.

KEYWORDS:

Adenoviral protease inhibitor; Epidemic keratoconjunctivitis (EKC); Irreversible inhibitor; Peptidomimetic; X-ray co-crystal structure

PMID:
25571794
DOI:
10.1016/j.bmcl.2014.12.057
[Indexed for MEDLINE]

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