Single atom changes in newly synthesized HIV protease inhibitors reveal structural basis for extreme affinity, high genetic barrier, and adaptation to the HIV protease plasticity
Single atom changes in newly synthesized HIV protease inhibitors reveal structural basis for extreme affinity, high genetic barrier, and adaptation to the HIV protease plasticity
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DOI：
10.1038/s41598-020-65993-z
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发表时间：
2020-06-30
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：
Bulut, Haydar;Hattori, Shin-ichiro;Mitsuya, Hiroaki
HIV-1 蛋白酶抑制剂 (Pls)，例如达芦那韦 (DRV)，是抗逆转录病毒治疗的关键组成部分。然而，HIV-1 经常对 Pls 产生耐药性。在这里，通过引入单原子变化（例如硫与氧的交换、P2'-环丙基氨基苯并噻唑（或恶唑）中的单键断裂和/或 P1-苯环）以及 DRV 支架周围的单氟或双氟原子的氟扫描，合成了七种新型 Pls。对与野生型蛋白酶（PRWT）和高度多重PI抗性相关的PRDRVP51R复合的Pls的X射线结构分析表明，通过在S2'-亚位点中形成最佳硫键和适应环丙基环，Pls更好地适应PR中的结构可塑性和抗性相关氨基酸取代。此外，与 DRV 相比，这些 Pls 显示出更高的细胞通透性和极高的抗 HIV-1 效力。我们的工作为开发具有高遗传屏障的 PI 抗性 HIV-1 变体高效的新型 Pls 提供了基础。
HIV-1 protease inhibitors (Pls), such as darunavir (DRV), are the key component of antiretroviral therapy. However, HIV-1 often acquires resistance to Pls. Here, seven novel Pls were synthesized, by introducing single atom changes such as an exchange of a sulfur to an oxygen, scission of a single bond in P2'-cyclopropylaminobenzothiazole (or-oxazole), and/or P1-benzene ring with fluorine scan of mono- or bis-fluorine atoms around DRV's scaffold. X-ray structural analyses of the Pls complexed with wild-type Protease (PRWT) and highly-multi-Pl-resistance-associated PRDRVP51R revealed that the Pls better adapt to structural plasticity in PR with resistance-associated amino acid substitutions by formation of optimal sulfur bond and adaptation of cyclopropyl ring in the S2'-subsite. Furthermore, these Pls displayed increased cell permeability and extreme anti-HIV-1 potency compared to DRV. Our work provides the basis for developing novel Pls with high potency against PI-resistant HIV-1 variants with a high genetic barrier.