Hybrids of Small-Molecule CD4 Mimics with Polyethylene Glycol Units as HIV Entry Inhibitors
Hybrids of Small-Molecule CD4 Mimics with Polyethylene Glycol Units as HIV Entry Inhibitors
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DOI：
10.1021/acs.jmedchem.0c01153
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发表时间：
2021-01-26
影响因子：
7.3
通讯作者：
Tamamura, Hirokazu
中科院分区：
文献类型：
--
作者：
Kobayakawa, Takuya;Tsuji, Kohei;Tamamura, Hirokazu
CD4模拟物是抑制gp120与CD4相互作用的小分子。我们已经开发了几种CD4模拟物。本文中，合成了由具有长烷基链或通过可自切割接头连接的PEG单元的CD4模拟物组成的杂合分子。在抗HIV活性中，用PEG单元修饰似乎比用长烷基链修饰更合适。因此，开发了具有通过不可裂解的接头连接的PEG单元的CD4模拟物的杂合分子，并且显示出高抗HIV活性和低细胞毒性。在恒河猴的药代动力学研究中，杂合化合物的PK特征比母体化合物更有效，肌内注射是比静脉注射更有用的维持CD4模拟物高血药浓度的给药途径。所提出的具有PEG单元的CD4模拟物的杂合分子在与中和抗体组合时将是实际有用的。
CD4 mimics are small molecules that inhibit the interaction of gp120 with CD4. We have developed several CD4 mimics. Herein, hybrid molecules consisting of CD4 mimics with a long alkyl chain or a PEG unit attached through a self-cleavable linker were synthesized. In anti-HIV activity, modification with a PEG unit appeared to be more suitable than modification with a long alkyl chain. Thus, hybrid molecules of CD4 mimics, with PEG units attached through an uncleavable linker, were developed and showed high anti-HIV activity and low cytotoxicity. In investigation of pharmacokinetics in a rhesus macaque, a hybrid compound had a more effective PK profile than that of the parent compound, and intramuscular injection was a more useful administration route to maintain the high blood concentration of the CD4 mimic than intravenous injection. The presented hybrid molecules of CD4 mimics with a PEG unit would be practically useful when combined with a neutralizing antibody.