Antiviral Activity and Crystal Structures of HIV-1 gp120 Antagonists.
Antiviral Activity and Crystal Structures of HIV-1 gp120 Antagonists.
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DOI：
10.3390/ijms232415999
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发表时间：
2022-12-15
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作为我们努力发现靶向HIV-1进入的药物的一部分，我们报告了gp120核心复合物中两种新型抑制剂的抗病毒活性和晶体结构。NBD-14204对所有临床分离株均表现出相似的抗病毒活性。IC50值在0.24 ~ 0.9µM范围内，总体平均值为0.47±0.03µM，对临床分离株的活性略好于对实验室适应HIV-1HXB2的活性（IC50 = 0.96±0.1µM）。此外，NBD-14208的抗病毒活性不太一致，其IC50值范围较宽（0.66-5.7µM），总体平均值为3±0.25µM，对B和D亚型（平均IC50 2.2-2.5µM）的活性优于a、C和Rec病毒（平均IC50 2.9-3.9µM）。NBD-14204的SI约为NBD-14208的10倍，是进一步优化的较好先导化合物。此外，我们对gp120的S375Y和S375H突变体进行了测试，发现这些突变体对NBD-14204和NBD-14208敏感。这些抑制剂也显示出对HIV-1逆转录酶的适度活性。此外，我们确定了这两种抑制剂在gp120核心配合物中的晶体结构。正如预期的那样，NBD-14204和NBD-14208主要在Phe43腔内结合。值得注意的是，由于支架的灵活性，这两种结构中噻唑环的电子密度定义不清，这表明这些化合物即使与Phe43腔结合也能保持大量的熵。
As part of our effort to discover drugs that target HIV-1 entry, we report the antiviral activity and crystal structures of two novel inhibitors in a complex with a gp120 core. NBD-14204 showed similar antiviral activity against all the clinical isolates tested. The IC50 values were in the range of 0.24–0.9 µM with an overall mean of 0.47 ± 0.03 µM, showing slightly better activity against the clinical isolates than against the lab-adapted HIV-1HXB2 (IC50 = 0.96 ± 0.1 µM). Moreover, the antiviral activity of NBD-14208 was less consistent, showing a wider range of IC50 values (0.66–5.7 µM) with an overall mean of 3 ± 0.25 µM and better activity against subtypes B and D (Mean IC50 2.2–2.5 µM) than the A, C and Rec viruses (Mean IC50 2.9–3.9 µM). SI of NBD-14204 was about 10-fold higher than NBD-14208, making it a better lead compound for further optimization. In addition, we tested these compounds against S375Y and S375H mutants of gp120, which occurred in some clades and observed these to be sensitive to NBD-14204 and NBD-14208. These inhibitors also showed modest activity against HIV-1 reverse transcriptase. Furthermore, we determined the crystal structures of both inhibitors in complexes with gp120 cores. As expected, both NBD-14204 and NBD-14208 bind primarily within the Phe43 cavity. It is noteworthy that the electron density of the thiazole ring in both structures was poorly defined due to the flexibility of this scaffold, suggesting that these compounds maintain substantial entropy, even when bound to the Phe43 cavity.
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DOI：
10.3390/v14102268
发表时间：
2022-10-16
期刊：
Viruses
影响因子：
--
作者：
Stoddart CA;Curreli F;Horrigan S;Altieri A;Kurkin AV;Debnath AK
通讯作者：
Debnath AK
影响因子：
7.3
作者：
Curreli F;Kwon YD;Zhang H;Scacalossi D;Belov DS;Tikhonov AA;Andreev IA;Altieri A;Kurkin AV;Kwong PD;Debnath AK
通讯作者：
Debnath AK
影响因子：
7.3
作者：
Curreli, Francesca;Kwon, Young Do;Debnath, Asim K.
通讯作者：
Debnath, Asim K.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
5.4
作者：
Blish, Catherine A.;Jalalian-Lechak, Zahra;Overbaugh, Julie
通讯作者：
Overbaugh, Julie