title: Nonpeptide inhibitors of measles virus entry.
abstract: Measles virus (MV) is one of the most infectious pathogens known. Despite the existence of a vaccine, over 500,000 deaths/year result from MV or associated complications. Anti-measles compounds could conceivably reverse these statistics. Previously, we described a homology model of the MV fusion protein trimer and a putative binding site near the head-neck region. The resulting model permitted the identification of two nonpeptidic entry inhibitors. Here, we present the design, synthesis, and bioevaluation of several series of fusion inhibitors and describe their structure-activity relationships (SAR). Five simply substituted anilides show low-microM blockade of the MV, one of which (AS-48) exhibits IC50 = 0.6-3.0 microM across a panel of wild-type MV strains found in the field. Molecular field topology analysis (MFTA), a 2D QSAR approach based on local molecular properties (atomic charges, hydrogen-bonding capacity and local lipophilicity), applied to the anilide series suggests structural modifications to improve potency.
authors.affiliation: Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, USA.
authors.forename: Aiming
authors.initials: A
authors.lastname: Sun
authors.forename: Andrew
authors.initials: A
authors.lastname: Prussia
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Zhan
authors.forename: Ernest E
authors.initials: EE
authors.lastname: Murray
authors.forename: Joshua
authors.initials: J
authors.lastname: Doyle
authors.forename: Li-Ting
authors.initials: LT
authors.lastname: Cheng
authors.forename: Jeong-Joong
authors.initials: JJ
authors.lastname: Yoon
authors.forename: Eugene V
authors.initials: EV
authors.lastname: Radchenko
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Palyulin
authors.forename: Richard W
authors.initials: RW
authors.lastname: Compans
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
authors.forename: Richard K
authors.initials: RK
authors.lastname: Plemper
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
mesh_terms: D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008459:Measles virus / Q000187:drug effects* / Q000502:physiology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D010446:Peptide Fragments / Q000737:chemistry; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000813:Anilides; D000998:Antiviral Agents; D010446:Peptide Fragments