Discovery of selective, small-molecule inhibitors of RNA complexes—1. The tat protein/TAR RNA complexes required for HIV-1 transcription

• Published in: Bioorganic & medicinal chemistry 1997-06, Vol.5 (6), p.1173-1184
• Main Authors: Mei, Houng-Yau, Mack, David P., Galan, Adam A., Halim, Nadia S., Heldsinger, Andrea, Loo, Joseph A., Moreland, David W., Sannes-Lowery, Kristin A., Sharmeen, Lamia, Truong, Hoa N., Czarnik, Anthony W.
• Format: Article
• Language: English
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(97)00064-3

We have developed a therapeutic program focusing on the inhibition of a human immunodeficiency virus-1 specific protein-RNA interaction. This program begins with a search for small organic molecules that would interfere with the binding of Tat protein to TAR RNA. The methodologies chosen to study the HIV-1 Tat-TAR interaction and inhibition include gel mobility shift assays, scintillation proximity assays, filtration assays, and mass spectrometry. These methods helped establish in vitro high-throughput screening assays which rapidly identified Tat-TAR inhibitors from our corporate compound library. Tat-activated reporter gene assays were then used to investigate the cellular activities of the Tat-TAR inhibitors. The cellular activity, selectivity, and toxicity data for select Tat-TAR inhibitors were determined. Evaluation of both the cellular data and the Tat-TAR inhibition results led to further testing in anti-HIV-1 infection assays.