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Discovery and structure-based optimization of adenain inhibitors.

ABSTRACT: The cysteine protease adenain is the essential protease of adenovirus and, as such, represents a promising target for the treatment of ocular and other adenoviral infections. Through a concise two-pronged hit discovery approach we identified tetrapeptide nitrile 1 and pyrimidine nitrile 2 as complementary starting points for adenain inhibition. These hits enabled the first high-resolution X-ray cocrystal structures of adenain with inhibitors bound and revealed the binding mode of 1 and 2. The screening hits were optimized by a structure-guided medicinal chemistry strategy into low nanomolar drug-like inhibitors of adenain.

SUBMITTER: Mac Sweeney A

PROVIDER: S-EPMC4137446 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Discovery and structure-based optimization of adenain inhibitors.

Mac Sweeney Aengus A Grosche Philipp P Ellis David D Combrink Keith K Erbel Paul P Hughes Nicola N Sirockin Finton F Melkko Samu S Bernardi Anna A Ramage Paul P Jarousse Nadine N Altmann Eva E

ACS medicinal chemistry letters 20140620 8

The cysteine protease adenain is the essential protease of adenovirus and, as such, represents a promising target for the treatment of ocular and other adenoviral infections. Through a concise two-pronged hit discovery approach we identified tetrapeptide nitrile 1 and pyrimidine nitrile 2 as complementary starting points for adenain inhibition. These hits enabled the first high-resolution X-ray cocrystal structures of adenain with inhibitors bound and revealed the binding mode of 1 and 2. The sc ...[more]

PMID: 25147618

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