10th Conference on Retroviruses and Opportunistic Infections Boston, MA USA - February 10 -14, 2003

Conf Retroviruses Opportunistic Infect 2003 Feb 10-14;10th: abstract no. 10
K Maeda¹, H Nakata ¹, T Miyakawa ¹, H Ogata ¹, Y Koh ¹, S Shibayama ², K Sagawa ², Y Takaoka ², J Moravek ³, Y Koyanagi ⁴, H Mitsuya ^1,5
1Kumamoto Univ Sch of Med, Japan; ²Ono Pharmaceutical Co LTD, Osaka, Japan; ³Moravek Biochemicals, Inc, Brea, CA; ⁴Tohoku Univ Graduate Sch of Med, Sendai, Japan; and ⁵Natl Cancer Inst, Bethesda, MD

BACKGROUND: CXCR4 and CCR5 are 2 major chemokine receptors HIV exploits in its entry to target cells, thereby serving as attractive targets for possible intervention of HIV infection. Certain spirodiketopiperazine derivatives bind to CCR5, block CC chemokine(CC)/CCR5 interactions, and inhibit HIV infection of CCR5⁺ cells. However, there is a concern that the sustained, long-term inhibition of CC/CCR5 interactions could produce significant adverse effects.

METHODS: Assays for inhibition of chemokine binding, cytosolic Ca²⁺ mobilization, chemotaxis, and HIV infection were conducted. Binding profiles of a variety of CCR5 inhibitors and their effects on CC/CCR5 interactions were also studied. AK602 was intraperitoneally administered to hu-PBM-NOD-SCID mice and tested for its in vivo anti-HIV activity.

RESULTS: AK602 exerted potent activity against a wide spectrum of laboratory and primary R5-HIV isolates including multi-drug resistant HIV_MDR (IC50 values of 0.2-0.6 nM), which was associated with its CCR5-binding affinity (KD values of ~2 nM) and potent inhibition of CCR5-gp120 binding. All previously reported CCR5 inhibitors tested (e.g., Sch-C, TAK779) fully blocked HIV infection as well as CC/CCR5 binding, while AK602, despite its much greater anti-HIV activity, partially suppressed the interactions at the highest possible concentrations. The AK602 binding site on CCR5 was located near the 2nd extracellular loop, possibly its C-terminal half (ECL-2B). AK602, once bound to CCR5²⁺ cells, remained on the cell surface for > 9 hrs after thorough washing, and blocked R5-HIV infection upon delayed HIV exposure. When intraperitoneally administered twice daily to R5-HIV-1JRFL-infected hu-PBM-NOD SCID mice, AK602 successfully suppressed HIV replication and blocked CD4²⁺ T-cell decrease. Preliminary pharmacokinetics revealed favorable oral bioavailability in rodents.

CONCLUSIONS: The present data strongly suggest that AK602 can potently block the infectivity and replication of a wide spectrum of R5-HIV with partial inhibition of CC/CCR5 interactions. Considering the possibility that the long-term inhibition of CC/CCR5 interactions could lead to compromised inflammation/immune reaction, the present data warrant further development of AK602 as a potential HIV-specific CCR-inhibiting therapeutic for HIV infection.

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