Nonpeptide inhibitors of measles virus entry.
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.
Sun
Aiming
A
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, USA.
Prussia
Andrew
A
Zhan
Weiqiang
W
Murray
Ernest E
EE
Doyle
Joshua
J
Cheng
Li-Ting
LT
Yoon
Jeong-Joong
JJ
Radchenko
Eugene V
EV
Palyulin
Vladimir A
VA
Compans
Richard W
RW
Liotta
Dennis C
DC
Plemper
Richard K
RK
Snyder
James P
JP
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
D000813:Anilides; D000998:Antiviral Agents; D010446:Peptide Fragments