4WX7

Crystal structure of adenovirus 8 protease with a nitrile inhibitor

Summary for 4WX7

• Entry DOI: 10.2210/pdb4wx7/pdb
• Descriptor: Protease, PVI, 3-[2-(3,5-dichlorophenyl)-2-methylpropanoyl]-N-(2-{[(2Z)-2-iminoethyl]amino}-2-oxoethyl)-4-methoxybenzamide, ... (4 entities in total)
• Functional Keywords: cysteine protease, inhibitor, covalent, hydrolase
• Biological source: Human adenovirus D serotype 8 (HAdV-8); More
• Total number of polymer chains: 4
• Total formula weight: 49656.69

Authors

Grosche, P.,Sirockin, F.,Mac Sweeney, A.,Ramage, P.,Erbel, P.,Melkko, S.,Bernardi, A.,Hughes, N.,Ellis, D.,Combrink, K.,Jarousse, N.,Altmann, E. (deposition date: 2014-11-13, release date: 2015-01-14, Last modification date: 2024-11-20)

Primary citation

Grosche, P.,Sirockin, F.,Mac Sweeney, A.,Ramage, P.,Erbel, P.,Melkko, S.,Bernardi, A.,Hughes, N.,Ellis, D.,Combrink, K.D.,Jarousse, N.,Altmann, E.
Structure-based design and optimization of potent inhibitors of the adenoviral protease.
Bioorg.Med.Chem.Lett., 25:438-443, 2015

PubMed 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.

PubMed: 25571794
DOI: 10.1016/j.bmcl.2014.12.057

Experimental method

X-RAY DIFFRACTION (2.4 Å)