Activity and structural analysis of GRL-117C: a novel small molecule CCR5 inhibitor active against R5-tropic HIV-1s
Activity and structural analysis of GRL-117C: a novel small molecule CCR5 inhibitor active against R5-tropic HIV-1s
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DOI：
10.1038/s41598-019-41080-w
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发表时间：
2019-03-18
影响因子：
4.6
通讯作者：
Mitsuya，Hiroaki
中科院分区：
文献类型：
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作者：
Nakata，Hirotomo;Maeda，Kenji;Mitsuya，Hiroaki
CCR 5是G蛋白偶联受体家族的成员，其充当R5嗜性HIV-1进入细胞的必需共受体，并且是针对HIV-1感染的治疗剂的经验证的靶标。本研究设计并合成了一系列新型小分子CCR 5抑制剂，并对其抗病毒活性进行了评价。GRL-117 C抑制野生型R5-HIV-1的复制，IC 50值为亚纳摩尔。这些衍生物保留了抗vicriviroc-resistant HIV-1的活性，但没有显示出抗maraviroc（MVC）-resistant HIV-1的活性。结构建模表明，化合物与CCR 5的结合发生在第二胞外环下的CCR 5的疏水腔中，并且对其结合至关重要的氨基酸与MVC的氨基酸几乎相似，这解释了病毒与MVC的交叉抗性。另一方面，一种衍生物GRL-10018 C，对HIV-1的作用较弱，但在抑制CC-趋化因子结合方面更有效，其双-THF部分占据了结合腔的上部区域，推测与CC-趋化因子产生更大的空间位阻。最近的研究表明，某些CCR 5抑制剂的其他独特的功能，如免疫调节特性和HIV-1潜伏期逆转特性，因此，在开发新的CCR 5抑制剂与独特的结合谱的持续努力是必要的。
CCR5 is a member of the G-protein coupled receptor family that serves as an essential co-receptor for cellular entry of R5-tropic HIV-1, and is a validated target for therapeutics against HIV-1 infections. In the present study, we designed and synthesized a series of novel small CCR5 inhibitors and evaluated their antiviral activity. GRL-117C inhibited the replication of wild-type R5-HIV-1 with a sub-nanomolar IC50value. These derivatives retained activity against vicriviroc-resistant HIV-1s, but did not show activity against maraviroc (MVC)-resistant HIV-1. Structural modeling indicated that the binding of compounds to CCR5 occurs in the hydrophobic cavity of CCR5 under the second extracellular loop, and amino acids critical for their binding were almost similar with those of MVC, which explains viral cross-resistance with MVC. On the other hand, one derivative, GRL-10018C, less potent against HIV-1, but more potent in inhibiting CC-chemokine binding, occupied the upper region of the binding cavity with itsbis-THF moiety, presumably causing greater steric hindrance with CC-chemokines. Recent studies have shown additional unique features of certain CCR5 inhibitors such as immunomodulating properties and HIV-1 latency reversal properties, and thus, continuous efforts in developing new CCR5 inhibitors with unique binding profiles is necessary.