title: Structure-based design and optimization of potent inhibitors of the adenoviral protease.
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.
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, 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: Aengus
authors.initials: A
authors.lastname: Mac Sweeney
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, 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: 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: Nicola
authors.initials: N
authors.lastname: Hughes
authors.affiliation: Novartis Institute for Biomedical Research, 6201 South Freeway, Fort Worth, TX 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, TX 76134-2099, United States.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Combrink
authors.affiliation: Novartis Institute for Biomedical Research, 4560 Horton Street, Emeryville, CA 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. Electronic address: eva.altmann@novartis.com.
authors.forename: Eva
authors.initials: E
authors.lastname: Altmann
mesh_terms: D000256:Adenoviridae / Q000187:drug effects / Q000201:enzymology*; D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; C091827:adenain
keywords: Adenoviral protease inhibitor; Epidemic keratoconjunctivitis (EKC); Irreversible inhibitor; Peptidomimetic; X-ray co-crystal structure