Design, synthesis and evaluation of small molecule CD4-mimics as entry inhibitors possessing broad spectrum anti-HIV-1 activity
Design, synthesis and evaluation of small molecule CD4-mimics as entry inhibitors possessing broad spectrum anti-HIV-1 activity
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DOI：
10.1016/j.bmc.2016.09.057
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发表时间：
2016-11-15
影响因子：
3.5
通讯作者：
Debnath, Asim K.
中科院分区：
文献类型：
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作者：
Curreli, Francesca;Belov, Dmitry S.;Debnath, Asim K.
自从我们首次发现靶向HIV-1 gp120的Phe43空腔的cd4模拟物NBD-556以来，我们和其他团队在设计具有病毒进入拮抗特性的新型cd4模拟物方面取得了相当大的进展。在我们继续努力的基础上，我们在之前报道的病毒进入拮抗剂NBD-11021的基础上合成了25个新的类似物。这些化合物首先在基于HIV-1 env -假病毒的单周期感染试验和多周期感染试验中进行了测试。这些新化合物中的四种显示出大大改善的抗病毒效力和细胞毒性。我们选择了两种最佳化合物45A （NBD-14009）和46A (NBD-14010)，对代表不同亚型临床分离株的51种env -pseudotype HIV-1进行了测试。这些化合物显示出明显的抗病毒效力宽度，IC50低至150 nM。这些化合物还抑制细胞间融合和细胞间HIV-1传播。该研究有望为设计针对HIV-1 gp120的Phe43空腔的更有效和选择性的HIV-1进入抑制剂铺平道路。(C) 2016 Elsevier Ltd.版权所有。
Since our first discovery of a CD4-mimic, NBD-556, which targets the Phe43 cavity of HIV-1 gp120, we and other groups made considerable progress in designing new CD4-mimics with viral entry-antagonist property. In our continued effort to make further progress we have synthesized twenty five new analogs based on our earlier reported viral entry antagonist, NBD-11021. These compounds were tested first in HIV-1 Env-pseudovirus based single-cycle infection assay as well as in a multi-cycle infection assay. Four of these new compounds showed much improved antiviral potency as well as cytotoxicity. We selected two of the best compounds 45A (NBD-14009) and 46A (NBD-14010) to test against a panel of 51 Env-pseudotyped HIV-1 representing diverse subtypes of clinical isolates. These compounds showed noticeable breadth of antiviral potency with IC50 of as low as 150 nM. These compounds also inhibited cell-to-cell fusion and cell-to-cell HIV-1 transmission. The study is expected to pave the way of designing more potent and selective HIV-1 entry inhibitors targeted to the Phe43 cavity of HIV-1 gp120. (C) 2016 Elsevier Ltd. All rights reserved.