Novel Central Nervous System (CNS)-Targeting Protease Inhibitors for Drug-Resistant HIV Infection and HIV-Associated CNS Complications
Novel Central Nervous System (CNS)-Targeting Protease Inhibitors for Drug-Resistant HIV Infection and HIV-Associated CNS Complications
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DOI：
10.1128/aac.00466-19
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发表时间：
2019-07-01
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：
Amano, Masayuki;Salcedo-Gomez, Pedro Miguel;Mitsuya, Hiroaki
目前尚无针对HIV-1相关中枢神经系统（CNS）并发症的特异性治疗方法。本文报道了三种新设计的CNS靶向HIV-1蛋白酶抑制剂（Pis）GRL-083-13、GRL-084-13和GRL-087-13，它们含有P1- 3，5-双-氟苯基或P1-对-单氟苯基环，和P2-双四氢呋喃（bis-THF）或P2-四氢吡喃-四氢呋喃（TP-THF），具有磺酰胺等排体，对野生型HIV-1毒株和主要临床分离株具有高度活性（50%有效浓度（EC 50），0.0002至近似0.003 μ M），具有最小的细胞毒性。这些CNS靶向的Pls有效地抑制了HIV-1变体的复制（EC 50，0.002至类似于0.047 μ M），所述HIV-1变体已被选择为在高浓度的常规HIV-1 Pls下繁殖。这种CNS靶向PI保持其对HIV-2（ROD）以及从长期治疗后不再对现有抗病毒方案有反应的艾滋病患者中分离的多药耐药临床HIV-1变体的抗病毒活性。长期药物选择实验表明，对这些CNS靶向Pls的耐药HIV-1的出现大大延迟。此外，CNS靶向Citation PI在测试化合物中显示出最有利的CNS渗透特性，包括各种FDA批准的抗HIV-1药物，如体外血脑屏障重建系统所评估的。晶体学分析表明，靶向CNS的Pl的P2部分的双环与HIV-1蛋白酶（PR）活性位点形成强氢键相互作用。此外，P1- 3，5-双-氟苯基和P1-对-单氟苯基环与PR的货车范德华接触均大于地瑞那韦（DRV）。这些数据表明，目前的CNS靶向PI具有治疗感染野生型和/或多药耐药HIV-1毒株的患者的理想功能，并可能成为HIV-1相关神经认知障碍（HAND）和其他CNS并发症的有希望的预防和/或治疗候选药物。
There is currently no specific therapeutics for the HIV-1-related central nervous system (CNS) complications. Here we report that three newly designed CNS-targeting HIV-1 protease inhibitors (Pis), GRL-083-13, GRL-084-13, and GRL-087-13, which contain a P1-3,5-bis-fluorophenyl or P1-para-monofluorophenyl ring, and P2-bistetrahydrofuran (bis-THF) or P2-tetrahydropyrano-tetrahydrofuran (Tp-THF), with a sulfonamide isostere, are highly active against wild-type HIV-1 strains and primary clinical isolates (50% effective concentration (EC50], 0.0002 to similar to 0.003 mu M), with minimal cytotoxicity. These CNS-targeting Pls efficiently suppressed the replication of HIV-1 variants (EC50, 0.002 to similar to 0.047 mu M) that had been selected to propagate at high concentrations of conventional HIV-1 Pls. Such CNS-targeting PIs maintained their antiviral activity against HIV-2(ROD) as well as multidrug-resistant clinical HIV-1 variants isolated from AIDS patients who no longer responded to existing antiviral regimens after long-term therapy. Long-term drug selection experiments revealed that the emergence of resistant-HIV-1 against these CNS-targeting Pls was substantially delayed. In addition, the CNS-targeting Citation PIs showed the most favorable CNS penetration properties among the tested com- pounds, including various FDA-approved anti-HIV-1 drugs, as assessed with the in vitro blood-brain barrier reconstruction system. Crystallographic analysis demonstrated that the bicyclic rings at the P2 moiety of the CNS-targeting Pls form strong hydrogen-bond interactions with HIV-1 protease (PR) active site. Moreover, both the P1-3,5-bis- fluorophenyl and P1-para-monofluorophenyl rings sustain greater van der Waals con- tacts with PR than in the case of darunavir (DRV). The data suggest that the present Copyright CNS-targeting PIs have desirable features for treating patients infected with wild-type and/or multidrug-resistant HIV-1 strains and might serve as promising preventive and/or therapeutic candidates for HIV-1-associated neurocognitive disorders (HAND) and other CNS complications.