Exploratory studies on soluble small molecule CD4 mimics as HIV entry inhibitors
Exploratory studies on soluble small molecule CD4 mimics as HIV entry inhibitors
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可溶性小分子 CD4 模拟物作为 HIV 进入抑制剂的探索性研究
DOI：
10.1016/j.bmc.2022.116616
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发表时间：
2022
影响因子：
3.5
通讯作者：
Tamamura Hirokazu
中科院分区：
文献类型：
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作者：
Tsuji Kohei;Kobayakawa Takuya;Konno Kiju;Masuda Ami;Takahashi Kohei;Ohashi Nami;Yoshimura Kazuhisa;Kuwata Takeo;Matsushita Shuzo;Harada Shigeyoshi;Tamamura Hirokazu
已经开发了几种抑制gp 120与CD 4相互作用的小分子CD 4模拟物。原始的CD 4模拟物如NBD-556，其具有芳环、N-二甲酰胺连接基和哌啶部分，具有显著的抗HIV活性，但其含有疏水芳环的结构在水中溶解性差。我们已经开发了用卤代吡啶基代替苯基的衍生物，如KKN-134，并发现它们具有优异的水溶性。检查的其他先导化合物是YIR-821，一种具有与哌啶环螺接的环己烷基团和哌啶氮原子上的胍基的化合物，及其PEG化衍生物TKB-002。YIR-821和TKB-002保留了有效的抗HIV活性。本文设计并合成了新的CD 4模拟物，其中苯基被卤代吡啶基取代，卤原子在不同位置，它们的衍生物在哌啶环上没有环己烷基团，它们的杂化分子具有PEG单元。这些化合物中的一些显示出显著更高的水溶性，同时保持一定水平的抗HIV活性。本研究为今后设计CD 4模拟分子提供了参考。
Several small molecule CD4 mimics, which inhibit the interaction of gp120 with CD4, have been developed. Original CD4 mimics such as NBD-556, which has an aromatic ring, an oxalamide linker and a piperidine moiety, possess significant anti-HIV activity but with their hydrophobic aromatic ring-containing structures are poorly soluble in water. We have developed derivatives with a halopyridinyl group in place of the phenyl group, such as KKN-134, and found them to have excellent aqueous solubility. Other leads that were examined are YIR-821, a compound with a cyclohexane group in aspiroattachment to a piperidine ring and a guanidino group on the piperidine nitrogen atom, and its PEGylated derivative, TKB-002. YIR-821 and TKB-002 retain potent anti-HIV activity. Here, new CD4 mimics, in which the phenyl group was replaced by a halopyridinyl group with the halogen atoms in different positions, their derivatives without a cyclohexane group on the piperidine ring and their hybrid molecules with PEG units were designed and synthesized. Some of these compounds show significantly higher aqueous solubility with maintenance of certain levels of anti-HIV activity. The present data should be useful in the future design of CD4 mimic molecules.