Orally active fusion inhibitor of respiratory syncytial virus.
BMS-433771 was found to be a potent inhibitor of respiratory syncytial virus (RSV) replication in vitro. It exhibited excellent potency against multiple laboratory and clinical isolates of both group A and B viruses, with an average 50% effective concentration of 20 nM. Mechanism-of-action studies demonstrated that BMS-433771 inhibits the fusion of lipid membranes during both the early virus entry stage and late-stage syncytium formation. After isolation of resistant viruses, resistance was mapped to a series of single amino acid mutations in the F1 subunit of the fusion protein. Upon oral administration, BMS-433771 was able to reduce viral titers in the lungs of mice infected with RSV. This new class of orally active RSV fusion inhibitors offers potential for clinical development.
Cianci
Christopher
C
The Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492, USA.
Yu
Kuo-Long
KL
Combrink
Keith
K
Sin
Ny
N
Pearce
Bradley
B
Wang
Alan
A
Civiello
Rita
R
Voss
Stacey
S
Luo
Guangxiang
G
Kadow
Kathy
K
Genovesi
Eugene V
EV
Venables
Brian
B
Gulgeze
Hatice
H
Trehan
Ashok
A
James
Jennifer
J
Lamb
Lucinda
L
Medina
Ivette
I
Roach
Julia
J
Yang
Zheng
Z
Zadjura
Lisa
L
Colonno
Richard
R
Clark
Junius
J
Meanwell
Nicholas
N
Krystal
Mark
M
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D024882:Drug Resistance, Viral; D005838:Genotype; D015726:Giant Cells / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000187:drug effects* / Q000235:genetics; D013696:Temperature; D014760:Viral Fusion Proteins / Q000096:biosynthesis; D010948:Viral Plaque Assay; D014764:Viral Proteins / Q000096:biosynthesis
D000998:Antiviral Agents; C482453:BMS 433771; D001562:Benzimidazoles; D018076:DNA, Complementary; D014760:Viral Fusion Proteins; D014764:Viral Proteins