Novel protease inhibitors (PIs) containing macrocyclic components and 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane that are potent against multi-PI-resistant HIV-1 variants in vitro.
Novel protease inhibitors (PIs) containing macrocyclic components and 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane that are potent against multi-PI-resistant HIV-1 variants in vitro.
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含有大环成分和 3(R),3a(S),6a(R)-双四氢呋喃氨基甲酸酯的新型蛋白酶抑制剂 (PI)，可在体外有效对抗多重 PI 耐药的 HIV-1 变体。
DOI：
10.1128/aac.01766-09
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发表时间：
2010
影响因子：
4.9
通讯作者：
Mitsuya,Hiroaki
中科院分区：
文献类型：
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作者：
Tojo,Yasushi;Koh,Yasuhiro;Amano,Masayuki;Aoki,Manabu;Das,Debananda;Kulkarni,Sarang;Anderson,DavidD;Ghosh,ArunK;Mitsuya,Hiroaki
具有大环结构特征的天然产物通常显示出有趣的生物学性质。结合大环的分子设计可能导致具有独特蛋白质-配体相互作用的分子。我们合成了一种新的含大环和双四氢呋喃基氨基甲酸酯的人类免疫缺陷病毒1型（HIV-1）蛋白酶抑制剂（PI）。其中4个化合物对HIV-1 LAI有较强的抑制活性，半数有效浓度（EC_（50））低至0.002 μM，细胞毒性极低。GRL-216和GRL-286可阻断由高达5 μM沙奎那韦、利托那韦、奈非那韦、洛匹那韦或阿扎那韦选择的HIV-1 NL 4 - 3变异体的复制;它们的EC 50为0.020至0.046 μM，对6种多重PI耐药临床HIV-1（HIVmPIr）变异体具有强效活性，EC 50为0.027至0.089 μM。GRL-216和GRL-286也与地瑞那韦一样有效地阻断HIV-1蛋白酶二聚化。当HIV-1 NL 4 - 3被GRL-216选择时，它的复制越来越差，并且在>0.26 μM GRL-216存在下无法复制，这表明GRL-216抗性HIV-1变体的出现大大延迟。在使用GRL-216（使用高达0.16 μM的GRL-216 [HIV 216 -0.16 μM]选择的HIV分离株）传代50次时，含有L10 I、L24 I、M46 L、V82 I和I84 V突变的HIV-1 NL 4 - 3对PI（包括地瑞那韦）保持相对敏感，其EC 50是每种药物对HIV-1 NL 4 -3的EC 50的3- 8倍。有趣的是，HIV 216 -0.16 μ M对替拉那韦的敏感性增加了10倍。GRL-216的蛋白质-配体X射线结构分析显示，与地瑞那韦相比，大环占据了蛋白酶结合腔的更大体积，并与V82和I84形成了更大的货车范德华相互作用。目前的数据保证了GRL-216作为治疗携带野生型和/或HIVmPIr的个体的潜在抗病毒剂的进一步开发。
Natural products with macrocyclic structural features often display intriguing biological properties. Molecular design incorporating macrocycles may lead to molecules with unique protein-ligand interactions. We generated novel human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a macrocycle andbis-tetrahydrofuranylurethane. Four such compounds exerted potent activity against HIV-1LAIand had 50% effective concentrations (EC50s) of as low as 0.002 μM with minimal cytotoxicity. GRL-216 and GRL-286 blocked the replication of HIV-1NL4-3variants selected by up to 5 μM saquinavir, ritonavir, nelfinavir, lopinavir, or atazanavir; they had EC50s of 0.020 to 0.046 μM and potent activities against six multi-PI-resistant clinical HIV-1 (HIVmPIr) variants with EC50s of 0.027 to 0.089 μM. GRL-216 and -286 also blocked HIV-1 protease dimerization as efficiently as darunavir. When HIV-1NL4-3was selected by GRL-216, it replicated progressively more poorly and failed to replicate in the presence of >0.26 μM GRL-216, suggesting that the emergence of GRL-216-resistant HIV-1 variants is substantially delayed. At passage 50 with GRL-216 (the HIV isolate selected with GRL-216 at up to 0.16 μM [HIV216-0.16 μM]), HIV-1NL4-3containing the L10I, L24I, M46L, V82I, and I84V mutations remained relatively sensitive to PIs, including darunavir, with the EC50s being 3- to 8-fold-greater than the EC50of each drug for HIV-1NL4-3. Interestingly, HIV216-0.16 μMhad 10-fold increased sensitivity to tipranavir. Analysis of the protein-ligand X-ray structures of GRL-216 revealed that the macrocycle occupied a greater volume of the binding cavity of protease and formed greater van der Waals interactions with V82 and I84 than darunavir. The present data warrant the further development of GRL-216 as a potential antiviral agent for treating individuals harboring wild-type and/or HIVmPIr.