2004 Fiscal Year Final Research Report Summary
Studies of novel small molecule anti-HIV-1 agents targeting the chemokine receptor CCR5
| Project/Area Number |
15390174
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Applied pharmacology
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| Research Institution | Kagoshima University |
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Principal Investigator |
BABA Masanori Kagoshima University, Graduate School of Medical and Dental Sciences, Professor, 大学院・医歯学総合研究科, 教授 (70181039)
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| Project Period (FY) |
2003 – 2004
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| Keywords | AIDS / HIV-1 / Chemotherapy / Chemokine receptor / CCR5 / Oral bioavailability |
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| Research Abstract |
In 1999, we have reported TAK-779 as a novel CCR5 antagonist with highly potent and selective inhibition of R5 HIV-1 replication in cell cultures. However, TAK-779 has poor oral bioavailability, and its development was discontinued by an unfavorable effect on injection sites. Our continuous efforts to find effective and orally bioavailable CCR5 antagonists have recently identified TAK-220 and TAK-652 through chemical modification of lead compounds discovered by a high throughput screening. The chemical structures of TAK-220 and TAK-652 are completely different each other. TAK-220 specifically inhibited ligand binding to CCR5 at nanomolar concentrations, whereas it did not inhibit ligand binding to other chemokine receptors. On the other hand, TAK-652 inhibited ligand binding to CCR2b as well as CCR5 at a similar concentration. Both compounds could inhibit CCR5-using HIV-1 replication including various clinical isolates at nanomolar concentrations, yet they did not show any inhibition of CXCR4-using HIV-1 replication. Furthermore, recombinant CCR5-using viruses carrying different subtype envelope proteins were found to be equally susceptible to these compounds. Single oral administration of TAK-652 up to 100 mg was safe and well-tolerated in humans. TAK-652 may be able to retain the plasma concentration sufficiently higher than the target concentration by once daily administration at a reasonable dose. Thus, TAK-652 has proved to be a promising therapeutic agent for HIV-1 infection, and the evaluation for its clinical efficacy in HIV-1-infected individuals appears to be worth conducting.
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