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Development of Novel Orally Bioavailable CXCR4 Antagonists, KRH-3955 and KRH-3140: Binding Specificity, Pharmacokinetics and Anti-HIV-1 Activity in vivo and in vitro
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Reported by Jules Levin
.... Single or daily administration of KRH-3955 and KRH-3140, respectively, efficiently protected hu-PBL-SCID mice from X4 HIV-1 infection.....
Yuetsu Tanaka*1, K Okuma1, R Tanaka1, S Kumakura2, A Shimoyamada2, K Hirose2, M Yanaka2, T Murakami3, and N Yamamoto3
1Univ of the Ryukyus, Okinawa, Japan; 2Kureha Corp. Tokyo, Japan; and 3Natl Inst of Infectious Diseases, Tokyo, Japan
In the late stage of HIV-1 infection, HIV-1 with phenotype of CXCR4 co-receptor tropism has been linked to a rapid progression to AIDS. Thus, an ART in combination with a CXCR4 antagonist that can interfere with the X4 HIV-1 infection may be advantageous in preventing AIDS. In this study, we have generated 2 orally bioavailable CXCR4 antagonists, KRH-3955 and KRH-3140, that showed extremely long and normal remaining time in vivo HH, respectively.
Using a hu-PBL-SCID mouse model, we found that single oral administration with KRH-3955 or daily administration with KRH-3140 in drinking water was capable of protecting the animals from X4 HIV-1 infection.
Antagonist activity and specificity of the drugs were determined using various chemokine receptor-expressing cells and their ligands. The binding sites of the antagonists on CXCR4 were estimated using a library of anti-human CXCR4 monoclonal antibodies. Their pharmacokinetic properties were determined in rats by ARG.
Preliminary in vitro anti-X4 HIV-1 activity was determined by using MT-4 cells and HIV-1IIIB. For in vivo study, C.B-17 SCID mice reconstituted with human peripheral blood mononuclear cells (PBMC) were used. KRH-3955 was administrated by mouth. once (10 mg/kg), while KRH-3140 was administrated daily by mouth in drinking water (15 to 20 mg/kg/day). The drug-treated hu-PBL-SCID mice were challenged with 5000 IU HIV-1NL4-3/animal intraperitoneally. 1 day after PBMC reconstitution. After 7 days from infection, cells were obtained from peritoneal lavage and cultured in vitro in IL-2-containing medium for determination of HIV-1 infection by p24 ELISA.
Results
KRH-3955 and KRH-3140 specifically inhibited the binding of SDF-1 to CXCR4-exressing cells but not those of the other chemokines to their receptors. The binding sites of KRH-3955 and KRH-3140 were localized to first, second, and/or third, and first and/or second extracellular loops, respectively.
KRH-3955 and KRH-3140 both active in vitro against X4 NL4-3 HIV-1:
- EC50 for KRH-3955: 0.9 nM
- EC50 for KRH-3140: 4.0 nM
The in vivo remaining time after oral administration of KRH-3955 was very long and that of KRH-3140 was normal.
No treatment-associated toxicities other than reversible increases in white blood cell count with increasing plasma drug concentrations.
Single or daily administration of KRH-3955 and KRH-3140, respectively, efficiently protected hu-PBL-SCID mice from X4 HIV-1 infection at both 2 and 8 weeks postchallenge with X4-tropic HIV, compared with control.
Authors concluded- KRH3955 and KRH-3140 are orally bioavailable CXCR4 antagonists with potent anti-X4 HIV-1 activities in vivo, indicating that these drugs may be desirable additives to an anti-HIV-1 therapy.
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