The Novel CXCR4 Antagonist KRH-3955 Is an Orally Bioavailable and Extremely Potent Inhibitor of Human Immunodeficiency Virus Type 1 Infection: Comparative Studies with AMD3100
The Novel CXCR4 Antagonist KRH-3955 Is an Orally Bioavailable and Extremely Potent Inhibitor of Human Immunodeficiency Virus Type 1 Infection: Comparative Studies with AMD3100
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DOI：
10.1128/aac.01727-08
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发表时间：
2009-07-01
影响因子：
4.9
通讯作者：
Yamamoto, Naoki
中科院分区：
文献类型：
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作者：
Murakami, Tsutomu;Kumakura, Sei;Yamamoto, Naoki
以前报道的CXCR4拮抗剂KRH-1636是一种利用(X4)人类免疫缺陷病毒1型(HIV-1)的CXCR4的有效和选择性的抑制剂，但由于其口服生物利用度较低，无法进一步开发为抗HIV-1的药物。新开发的KRH-3955是一种KRH-1636衍生物，口服时具有比AMD3100和KRH-1636更强大的抗HIV-1活性。该化合物非常有效地抑制X4HIV-1的复制，包括来自不同捐赠者的激活的外周血单核细胞中的临床分离株。它还对含有逆转录酶和蛋白水解酶耐药突变的重组X4 HIV-1和具有恩福韦德耐药突变的包膜具有活性。KRH-3955既可抑制SDF-1α与CXCR4的结合，又可通过受体抑制钙信号转导。KRH-3955抑制识别CXCR4的第一、第二或第三细胞外环的抗CXCR4单抗的结合。该化合物在大鼠体内的口服生物利用度为25.6%，其口服给药可阻止X4 HIV-1在人外周血淋巴细胞-严重联合免疫缺陷小鼠系统中的复制。因此，KRH-3955是一种很有前途的HIV-1感染和艾滋病的新药物。
The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1 alpha binding to CXCR4 and Ca2+ signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.