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Anti-viral Characterization in vitro of a Novel Maturation Inhibitor, MPC-9055
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Reported by Jules Levin
CROI 209 Feb 8-12 Montreal
Vijay Baichwal, Harry Austin, Brita Brown, Rena McKinnon, Kraig Yager,
Vijay Kumar, David Gerrish, Mark Anderson and Robert Carlson
Myriad Pharmaceuticals Inc., Salt Lake City, UT, USA
AUTHOR CONCLUSIONS
♦ MPC-9055 potently inhibits HIV replication in vitro
♦ Broad range of activity against clinical isolates including drug resistant strains
♦ Inhibits virus maturation by blocking Gag cleavage at the CA-SP1 site
♦ Mechanism of action is distinct from current HIV therapies
♦ In clinical development (Abstract #: K-119)
ABSTRACT
Background: There is a continuing need for anti-HIV drugs with novel mechanisms because of development of resistance to existing therapies. MPC-9055 was discovered in a medicinal chemistry program as a potent, broadacting small molecule inhibitor of HIV-1 maturation and is now in Phase I clinical development.
Methods: Antiviral replication assays in human PBMCs were used to determine
the potency, range of action and activity of MPC-9055 against clinical drug-resistant isolates. Cytoprotection assays were used to analyze the mode of action and to isolate virus resistant to MPC-9055. Western blot with a p24
antibody was used to investigate effects of MPC-9055 on Gag processing.
Results: MPC-9055 had potent antiviral activity against the IIIB strain of HIV in
a PBMC assay (IC50 7 nM) and against the NL4-3 and RF strains in cytoprotection assays with MT-4 and CEM-SS cells, respectively (EC50 10 and
13 nM). MPC-9055 exhibited efficacy against a broad range of clinical isolates
from groups M, N and O, subtypes A to G, and receptor tropisms (X4, R5 and
R5/X4). Importantly, it was also active against RT- and PI-resistant isolates and MDR strains with IC50 values ranging from 8 to 170 nM. Mode of action studies indicate that MPC-9055 acts at a late step in the viral life cycle with selective inhibition of Gag processing and HIV maturation. MPC-9055 specifically blocked processing of CA-SP1 Gag intermediate to mature CA and reduced infectivity of virions produced from 293T cells transfected with a proviral genome. Treatment of latently-infected ACH-2 cells with MPC-9055 resulted in production of noninfectious virus. Engineered mutations at the CA-SP1cleavage sites L363F and A364V were 60 and 395-fold less active, respectively, against MPC-9055 in a cytoprotection assay in MT-4 cells. In an analogous manner, virus selected for resistance to MPC-9055 by serial passage in vitro had the single amino acid change A364V at the CA-SP1 junction.
Conclusions: MPC-9055 is a potent anti-HIV agent with a broad range of action. It has a novel mechanism of action and targets the last step in Gag processing, cleavage of CA-SP1 to CA. MPC-9055 is also active against RT and PI-resistant strains. Based upon this efficacy profile and novel mechanism of action, MPC-9055 is a promising new HIV therapeutic.
Background
MPC-9055 discovered in a medicinal chemistry program is a small molecule inhibitor of HIV-1 maturation that is in clinical development (Abstract #: K-119)
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