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CCR5 Antagonist TD-0680 Uses a Novel Mechanism for Enhanced Potency against HIV-1 Entry, Cell-mediated Infection, and a Resistant Variant
- Source :
- Journal of Biological Chemistry. 287:16499-16509
- Publication Year :
- 2012
- Publisher :
- Elsevier BV, 2012.
-
Abstract
- Regardless of the route of transmission, R5-tropic HIV-1 predominates early in infection, rendering C-C chemokine receptor type 5 (CCR5) antagonists as attractive agents not only for antiretroviral therapy but also for prevention. Here, we report the specificity, potency, and underlying mechanism of action of a novel small molecule CCR5 antagonist, TD-0680. TD-0680 displayed the greatest potency against a diverse group of R5-tropic HIV-1 and SIV strains when compared with its prodrug, TD-0232, the Food and Drug Administration-approved CCR5 antagonist Maraviroc, and TAK-779, with EC(50) values in the subnanomolar range (0.09-2.29 nm). Importantly, TD-0680 was equally potent at blocking envelope-mediated cell-cell fusion and cell-mediated viral transmission as well as the replication of a TAK-779/Maraviroc-resistant HIV-1 variant. Interestingly, TD-0232 and TD-0680 functioned differently despite binding to a similar transmembrane pocket of CCR5. Site-directed mutagenesis, drug combination, and antibody blocking assays identified a novel mechanism of action of TD-0680. In addition to binding to the transmembrane pocket, the unique exo configuration of this molecule protrudes and sterically blocks access to the extracellular loop 2 (ECL2) region of CCR5, thereby interrupting the interaction between virus and its co-receptor more effectively. This mechanism of action was supported by the observations of similar TD-0680 potency against CD4-dependent and -independent SIV strains and by molecular docking analysis using a CCR5 model. TD-0680, therefore, merits development as an anti-HIV-1 agent for therapeutic purposes and/or as a topical microbicide for the prevention of sexual transmission of R5-tropic HIV-1.
- Subjects :
- Sexual transmission
Receptors, CCR5
Anti-HIV Agents
viruses
HIV Infections
CCR5 receptor antagonist
Pharmacology
Biology
Virus Replication
Microbiology
Biochemistry
Protein Structure, Secondary
Cell Line
Maraviroc
chemistry.chemical_compound
Cyclohexanes
Viral entry
medicine
Humans
Potency
Molecular Biology
Sulfonamides
Binding Sites
Drug discovery
virus diseases
Cell Biology
Triazoles
Virus Internalization
Amides
Entry inhibitor
Quaternary Ammonium Compounds
Mechanism of action
chemistry
CCR5 Receptor Antagonists
HIV-1
medicine.symptom
Tropanes
medicine.drug
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 287
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....a8bc101a36c1024765e5b36f8bdb7914