AEGiS-13IAC: KRH-1120, a small- CXCR4 antagonistic nonpeptide molecule, with highly potent and selective anti-HIV-1 activity.

13th International AIDS Conference

Durban, South Africa - July 9-July 14, 2000

KRH-1120, a small- CXCR4 antagonistic nonpeptide molecule, with highly potent and selective anti-HIV-1 activity.

Int Conf AIDS 2000 Jul 9-14; 13:(abstract no. WeOrA535)

Ichiyama K, Hirose K, Yokoyama S, Bannai K, Edamatsu T, Yanaka M, Niitani M, Yamamoto N
K. Ichiyama, Tokyo Medical and Dental University, School of Medicine, 1-5-45 Yushima Bunkyo-ku, Tokyo 113 8519, Japan, Tel.: +81 3 580 351 78, Fax: +81 3 580 301 24, E-mail: ichiyama.mmb@med.tmb.ac.jp

BACKGROUND: To determine the effects of KRH-1120, a nonpeptide compound with a small molecular weight, on the binding of SDF-1 to CXCR4 and T-cell line-tropic HIV-1 replication.

METHODS: The effects of KRH-1120 on the SDF-1 binding and blocking of Ca2+ signaling were studied with CXCR4-expressing HOS cells. HIV-1 replication was determined in infected and uninfected peripheral blood mononuclear cells (PBMC) and a human T-cell line, MT-4. Several laboratory strains and clinical HIV-1 isolates including X4 (HTLV-IIIB and NL4-3) and R5 (JR-CSF and JR-FL) viruses were utilized for infection. HIV-1 replication was monitored by MTT assay, p24 antigen and HIV-1 mRNA production.

RESULTS: KRH-1120 antagonized the binding of SDF-1 to CXCR4 in HOS cells and blocked CXCR4-mediated Ca2+ signaling at nanomolar concentrations The inhibition of alpha-chemokine receptors by KRH-1120 appeared to be specific to CXCR4 because the compound did not affect CCR5, CCR3, or CCR4. Thus, KRH-1120 represented highly potent and selective inhibition of X4 HIV-1 replication without showing any cytotoxicity to the host cells. The compound inhibited the replication of X4 HIV-1 clinical isolates as well as a laboratory strain in PBMC, though it was totally inactive against R5 HIV-1.

CONCLUSIONS: KRH-1120 is a potent inhibitor HIV-1 replication and is considered to be orally-available based on its chemical structures. Hence, it deserves further investigation as a potential therapeutic agent in the treatment of HIV-1-infected patients in combination with members of drugs utilized in HAART.

Keywords: AEGIS, HIV-1, Virus Replication, Receptors, Chemokine, Chemokines, CXC, T-Lymphocytes, stromal cell-derived factor-1alpha, Human, virology
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