1,2,3,4‐Tetrahydroisoquinolines as inhibitors of HIV‐1 integrase and human LEDGF/p75 interaction,Chemical Biology & Drug Design

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1,2,3,4‐Tetrahydroisoquinolines as inhibitors of HIV‐1 integrase and human LEDGF/p75 interaction
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2018-03-15 , DOI: 10.1111/cbdd.13175
Anu George ₁ , Alavala Gopi Krishna Reddy ₂ , Gedu Satyanarayana ₂ , Nidhanapati K Raghavendra ₁

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Alkaloids are a class of organic compounds with a wide range of biological properties, including anti‐HIV activity. The 1,2,3,4‐tetrahydroisoquinoline is a ubiquitous structural motif of many alkaloids. Using a short and an efficient route for synthesis, a series of 1,2,3,4‐tetrahydroisoquinolines/isoquinolines was developed. These compounds have been analysed for their ability to inhibit an important interaction between HIV‐1 integrase enzyme (IN) and human LEDGF/p75 protein (p75) which assists in the viral integration into the active genes. A lead compound 6d is found to inhibit the LEDGF/p75‐IN interaction in vitro with an IC₅₀ of ~10 μm. Molecular docking analysis of the isoquinoline 6d reveals its interactions with the LEDGF/p75‐binding residues of IN. Based on an order of addition experiment, the binding of 6d or LEDGF/p75 to IN is shown to be mutually exclusive. Also, the activity of 6d in vitro is found to be unaffected by the presence of a non‐specific DNA. As reported earlier for the inhibitors of LEDGF/p75‐IN interaction, 6d exhibits a potent inhibition of both the early and late stages of HIV‐1 replication. Compound 6d differing from the known inhibitors in the chemical moieties and interactions with CCD could potentially be explored further for developing small molecule inhibitors of LEDGF/p75‐IN interaction having a higher potency.

中文翻译：

1,2,3,4-四氢异喹啉类药物作为HIV-1整合酶和人类LEDGF / p75相互作用的抑制剂

生物碱是一类具有广泛生物学特性（包括抗HIV活性）的有机化合物。1,2,3,4-四氢异喹啉是许多生物碱普遍存在的结构基序。使用短而有效的合成途径，开发了一系列1,2,3,4-四氢异喹啉/异喹啉。已对这些化合物抑制HIV-1整合酶（IN）和人类LEDGF / p75蛋白（p75）之间重要相互作用的能力进行了分析，这有助于将病毒整合到活性基因中。铅化合物6D被发现能抑制与IC在体外LEDGF / P75-IN相互作用₅₀的〜10μ米。异喹啉6d的分子对接分析揭示了其与IN的LEDGF / p75结合残基的相互作用。根据添加实验的顺序，显示6d或LEDGF / p75与IN的结合是互斥的。另外，发现6d的体外活性不受非特异性DNA的影响。如先前报道的有关LEDGF / p75-IN相互作用抑制剂的报道，6d对HIV-1复制的早期和晚期均表现出有效的抑制作用。化合物6d在化学部分上与已知抑制剂不同，并且与CCD的相互作用可能会被进一步探索，以开发具有更高效力的LEDGF / p75-IN相互作用的小分子抑制剂。

更新日期：2018-03-15

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