title: First generation inhibitors of the adenovirus proteinase.
abstract: As there are more than 50 adenovirus serotypes, the likelihood of developing an effective vaccine is low. Here we describe inhibitors of the adenovirus proteinase (AVP) with the ultimate objective of developing anti-adenovirus agents. Inhibitors were identified via structure-based drug design using as druggable sites the active site and a conserved cofactor pocket in the crystal structures of AVP. A lead compound was identified that had an IC50 of 18 μM. One of eight structural derivatives of the lead compound had an IC50 of 140 nM against AVP and an IC50 of 490 nM against the AVP with its cofactor bound.
authors.affiliation: Biosciences Department, Brookhaven National Laboratory, 50 Bell Avenue, Upton, NY 11973, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: McGrath
authors.forename: Vito
authors.initials: V
authors.lastname: Graziano
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Zabrocka
authors.forename: Walter F
authors.initials: WF
authors.lastname: Mangel
mesh_terms: D000256:Adenoviridae / Q000201:enzymology*; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors
keywords: 11-amino acid peptide from the C-terminus of adenovirus precursor protein pVI; AVP; AVP–pVIc; Adenovirus proteinase; CT-pocket; Inhibitors; NT-pocket; RFI; Structure-based drug design; adenovirus proteinase; covalent complex between AVP and pVIc; induced pocket on surface of AVP–pVIc complex where C-terminal residues of pVIc interact with AVP; pVI; pVIc; pocket on surface of AVP where N-terminal residues of pVIc interact with AVP; relative fluorescence intensity; the precursor to protein VI