4WX7

Crystal structure of adenovirus 8 protease with a nitrile inhibitor

4WX7 の概要

• エントリーDOI: 10.2210/pdb4wx7/pdb
• 分子名称: Protease, PVI, 3-[2-(3,5-dichlorophenyl)-2-methylpropanoyl]-N-(2-{[(2Z)-2-iminoethyl]amino}-2-oxoethyl)-4-methoxybenzamide, ... (4 entities in total)
• 機能のキーワード: cysteine protease, inhibitor, covalent, hydrolase
• 由来する生物種: Human adenovirus D serotype 8 (HAdV-8); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 49656.69

構造登録者

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. (登録日: 2014-11-13, 公開日: 2015-01-14, 最終更新日: 2024-11-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.4 Å)