HIV-1 has an RNA genome that is generated by the transcription of its proviral DNA through a series of events starting from the viral transcriptional activator Tat. Tat interacts specifically with host cyclin T1 (CycT1), a component of the RNAPII transcription elongator factor complex, which enhances binding of the complex to cis-acting transactivation-responsive (TAR) RNA at the 5′ end of nascent HIV-1 transcripts. RNAPII then begins the elongation of HIV-1 transcripts. The interactions between the elongation factor complex, Tat and TAR RNA are therefore crucial for replication of the HIV-1 genome. Hamasaki et al. searched for compounds that could bind the Tat/TAR RNA recognition motif (TRM) of CycT1 by in silico screening of 3 million compounds. The authors docked members of the library to a TRM identified in a homology model of the tripartite complex. Two of the hits from the screen and a related compound (C3) inhibited HIV-1 replication in vitro. The results of a competition assay validated that C3 targets the Tat-CycT1 interface. C3 specifically inhibited Tat-mediated HIV-1 transcription and also suppressed Tat-induced phosphorylation of RNAPII, which is essential for its activity on HIV-1 transcripts. C3-based compounds may prove useful in combination with anti–HIV-1 drugs that act by other mechanisms.
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Bucci, M. Hits for Tat. Nat Chem Biol 9, 215 (2013). https://doi.org/10.1038/nchembio.1220