title: 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.
authors.affiliation: Novartis Institute for Biomedical Research , Novartis Campus, CH-4002 Basel, Switzerland.
authors.forename: Aengus
authors.initials: A
authors.lastname: Mac Sweeney
authors.affiliation: Novartis Institute for Biomedical Research , Novartis Campus, CH-4002 Basel, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Grosche
authors.affiliation: Novartis Institute for Biomedical Research , 6201 South Freeway, Fort Worth, Texas 76134-2099, United States.
authors.forename: David
authors.initials: D
authors.lastname: Ellis
authors.affiliation: Novartis Institute for Biomedical Research , 6201 South Freeway, Fort Worth, Texas 76134-2099, United States.
authors.forename: Keith
authors.initials: K
authors.lastname: Combrink
authors.affiliation: Novartis Institute for Biomedical Research , Novartis Campus, CH-4002 Basel, Switzerland.
authors.forename: Paul
authors.initials: P
authors.lastname: Erbel
authors.affiliation: Novartis Institute for Biomedical Research , Novartis Campus, CH-4002 Basel, Switzerland.
authors.forename: Nicola
authors.initials: N
authors.lastname: Hughes
authors.affiliation: Novartis Institute for Biomedical Research , Novartis Campus, CH-4002 Basel, Switzerland.
authors.forename: Finton
authors.initials: F
authors.lastname: Sirockin
authors.affiliation: Novartis Institute for Biomedical Research , Novartis Campus, CH-4002 Basel, Switzerland.
authors.forename: Samu
authors.initials: S
authors.lastname: Melkko
authors.affiliation: Novartis Institute for Biomedical Research , Novartis Campus, CH-4002 Basel, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Bernardi
authors.affiliation: Novartis Institute for Biomedical Research , Novartis Campus, CH-4002 Basel, Switzerland.
authors.forename: Paul
authors.initials: P
authors.lastname: Ramage
authors.affiliation: Novartis Institute for Biomedical Research , 4560 Horton Street, Emeryville, California 94608-2916, United States.
authors.forename: Nadine
authors.initials: N
authors.lastname: Jarousse
authors.affiliation: Novartis Institute for Biomedical Research , Novartis Campus, CH-4002 Basel, Switzerland.
authors.forename: Eva
authors.initials: E
authors.lastname: Altmann
keywords: Adenoviral protease; adenoviral infection; inhibitor X-ray cocrystal structure; structure-based design