Paper # 518|
Antiviral Activity of a New Small Molecule HIV-1 Attachment Inhibitor, BMS-626529, the Parent of BMS-663068
B Nowicka-Sans1, Y-F Gong1, H-T Ho1, R Colonno1, P-F Lin1, M Wind-Rotolo2, J Kadow1, N Meanwell1, R Nettles3, and Mark Krystal*1
1Bristol-Myers Squibb PRI, Wallingford, CT, US; 2Bristol-Myers Squibb PRI, Lawrenceville, NJ, US; and 3Bristol-Myers Squibb PRI, Hopewell, NJ, US
Background: BMS-626529 is a next-generation HIV-1
attachment inhibitor (AI) that binds to the gp120 glycoprotein of the viral
envelope and interferes with virus attachment to the cellular receptor CD4. In
vivo antiviral activity of BMS-626529 has been assessed in a monotherapy
trial with an oral prodrug, BMS-663068.
Methods: Activity against laboratory HIV strains was
examined in T cell lines with/without 40% human serum (HS). Clinical isolates
were examined in freshly prepared peripheral blood mononuclear cells (PBMC).
Susceptibility of patient-derived envelopes was tested by Monogram Biosciences
(PhenoSense Entry). A gp120/CD4 ELISA, micro BioSpin binding, and sedimentation
equilibrium analysis were employed in biochemical studies.
Results: BMS-626529 binds directly to gp120 and
inhibits the binding of soluble CD4 to gp120, with an IC50 of 14 nM.
The displacement of [3H]BMS-626529
from gp120 by excess soluble CD4 required about 8 hours, which is ~16-fold
longer than that observed with BMS-488043, an earlier AI. BMS-626529
exhibits a spectrum of activity against clinical isolates of HIV-1 within and
between subtypes and is active against both R5 and X4 viruses. In the
PhenoSense assay, EC50 of envelopes from clinical isolates ranged
from 67 pM to >0.1 μM. In a screen of 157 subtype B and 36 C viruses,
93 to 94% of viruses from both subtypes exhibited EC50 less than 10
nM, with 73% of the clade B and 42% of the clade C viruses exhibiting EC50
of less than 1 nM. Similar ranges were observed with clades A, AG, BF, F, and
F1 (although with fewer samples). BMS-626529 was not active against any subtype
AE virus examined or against HIV-2, and is non-cytotoxic in multiple human cell
lines. Finally, in combination with 24 marketed and investigational anti-HIV
agents, including other entry inhibitors, BMS-626529 yielded synergistic or
additive antiviral effects in all assays.
Conclusions: BMS-626529 is a potent and selective
member of the novel class of AI, superior to the previous clinical candidate,
BMS-488043. The favorable antiviral profile of BMS-626529 supports further
development of its oral prodrug, BMS-663068.