1,2,3,4-tetrahydroisoquinolines as inhibitors of HIV-1 integrase and human LEDGF/p75 interaction

Abstract

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.

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An isoquinoline compound 6d (ethyl-1-benzyl-7-methoxyisoquinoline-4-carboxylate, shown as a stick model) has been identified as a lead molecule for inhibiting the interaction between human LEDGF/p75 and HIV-1 integrase (IN). Compound 6d inhibits formation of a LEDGF/p75-IN complex with an IC50 of 10.4±3.8 μM in vitro. Similar to LEDGINs identified earlier, the activity of 6d has been characterized at both the early and late stages of HIV-1 replication. Molecular docking analysis reveals that 6d occupies the LEDGF/p75 binding site on a IN dimer (the monomers are shown in red and green ribbons). The in vitro order-of-addition experiment supports an overlap in the binding site for LEDGF/p75 and 6d on IN.

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