Indole-Based Compounds as a New Class of Allosteric Inhibitors of HIV-1 Integrase
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Date
2016-05
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The Ohio State University
Abstract
HIV-1 integrase (IN) is an important therapeutic target in the fight against AIDS as its function is essential for viral replication. Constant mutations in the HIV-1 genome allow the virus to gain resistance to current antiretroviral therapies. Therefore, there is a continued need to discover new therapeutic compounds with alternative mechanisms of action. One such mechanism is to allosterically inactivate IN through a small molecule inhibitor promoting aberrant IN multimerization. IN functions as a tetramer, and if it is multimerized further by a compound then IN will no longer be able to carry out its function properly. Another mechanism is to interfere with HIV-1 IN binding to its principal cellular interacting partner lens epithelium-derived growth factor (LEDGF)/p75. The aim of this study was to utilize novel homogeneous time-resolved fluorescence (HTRF)-based assays to identify promising new lead compounds and dissect their mechanism of action. Six indole-based compounds were initially analyzed by HTRF-based LEDGF/p75-dependent integration assay and compound KF113 with an IC50 value of ~ 4.5 µM was selected for further structure-activity relationships studies. KF113 exhibited a multimodal mechanism of action as this compound inhibited IN binding to LEDGF/p75 as well as induced aberrant IN multimerization. Importantly, KF113 was fully active against mutant A128T IN, which confers marked resistance to current quinoline-based allosteric IN inhibitors. These results indicate that our innovative HTRF-based assays allow for efficient identification of promising inhibitors of HIV-1 IN. Furthermore, the indole-based compounds are promising leads for further development and could ultimately lead to the discovery of novel anti-HIV-1 drugs.
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Keywords
drug development, pharmaceutical sciences, HIV, integrase