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Homogeneous high-throughput screening assays for HIV-1 integrase 3beta-processing and strand transfer activities.

Wang, Yu and Klock, Heath and Yin, Hong and Wolff, Karen and Bieza, Kimberly and Niswonger, Kirk and Matzen, Jason and Gunderson, Drew and Hale, Joanna and Lesley, Scott and Kuhen, Kelli and Caldwell, Jeremy and Brinker, Achim (2005) Homogeneous high-throughput screening assays for HIV-1 integrase 3beta-processing and strand transfer activities. Journal of Biomolecular Screening : the official journal of the Society for Biomolecular Screening, 10 (5). pp. 456-462. ISSN 1087-0571

Abstract

HIV-1 integrase (HIV-IN) is a well-validated antiviral drug target catalyzing a multistep reaction to incorporate the HIV-1 provirus into the genome of the host cell. Small molecule inhibitors of HIV-1 integrase that specifically target the strand transfer step have demonstrated efficacy in the suppression of virus propagation. However, only few specific strand transfer inhibitors have been identified to date, and the need to screen for novel compound scaffolds persists. Here, the authors describe 2 homogeneous time-resolved fluorescent resonance energy transfer-based assays for the measurement of HIV-1 integrase 3'-processing and strand transfer activities. Both assays were optimized for high-throughput screening formats, and a diverse library containing more than 1 million compounds was screened in 1536-well plates for HIV-IN strand transfer inhibitors. As a result, compounds were found that selectively affect the enzymatic strand transfer reaction over 3beta processing. Moreover, several bioactive molecules were identified that inhibited HIV-1 reporter virus infection in cellular model systems. In conclusion, the assays presented herein have proven their utility for the identification of mechanistically interesting and biologically active inhibitors of HIV-1 integrase that hold potential for further development into potent antiviral drugs.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: HIV-1, antivirals, TR-FRET, strand transfer, 3′ processing
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Date Deposited: 14 Dec 2009 14:02
Last Modified: 31 Jan 2013 01:22
URI: https://oak.novartis.com/id/eprint/247

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