402-T. Identification of CCR5 Co-Receptor Inhibitors that Potently and Selectively Block HIV-1 Replication

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Session 58 Poster Session
Entry Inhibitors
Session Time: 4:30-6:30 pm
Room 4E-F

402-T.

Identification of CCR5 Co-Receptor Inhibitors that Potently and Selectively Block HIV-1 Replication
W. Olson*¹, T. Dragic², B. O’Hara¹, K. Nagashima¹, F. Tsamis², M. Westby³, and N. Cammack³
¹Progenics Pharmaceuticals, Inc., Tarrytown, NY; ²Albert Einstein Coll. of Med., Bronx, NY; and ³Roche Discovery, Palo Alto, CA

Background: The CC-chemokine receptor CCR5 is a requisite fusion co-receptor for primary HIV-1 isolates. As a 7-transmembrane G-protein-coupled receptor with limited tissue distribution, CCR5 represents a promising target for a new class of viral entry inhibitors. High-throughput screens for inhibitors of chemokine binding have yielded a number of CCR5 antagonists that block HIV-1 replication in vitro, but to date there has been no description of small molecule CCR5-targeting agents that block HIV-1 replication without antagonizing chemokine binding.
Methods: We performed high-throughput screening of the Roche sample collection using a homogeneous cell-based resonance energy transfer (RET) assay that recapitulates all stages of HIV-1 envelope glycoprotein-mediated membrane fusion. Active compounds from the primary screen and analogs thereof were evaluated for their antiviral, anti-chemokine and other properties in a cascade of secondary assays.
Results: Compounds were identified that specifically block CCR5-mediated, but not CXCR4-mediated, HIV-1 cell-cell and virus-cell fusion with nanomolar potency. The latter studies employed a series of env-complemented luciferase reporter viruses as well as primary HIV-1 isolates. Notably, unlike natural ligand-binding assays, this approach could identify CCR5-targeting agents that selectively block HIV-1 replication but not chemokine binding.
Conclusions: Using a high-throughput assay for HIV-1 membrane fusion, we identified small-molecule CCR5 inhibitors that selectively block CCR5’s interactions with HIV-1. These compounds may represent promising lead candidates for further optimization as members of a new generation of antiretroviral agents.