Efficient transcription of the HIV viral promoter requires binding of Tat, a virally-encoded transactivator protein, to bind to the HIV TAR RNA, the viral transactivator response element. Because the main cause of treatment failure is due to the reactivation of the virus from latently infected cells, which requires the Tat-TAR interaction, the discovery of inhibitors of the Tat-TAR interaction is of significant interest to new treatment options. Our group has recently identified structurally constrained cyclic peptides that bind to TAR RNA specifically and with unprecedented affinity. The compounds are proteolytically stable, non-toxic, potent inhibitors of viral replication that act by a new dual mechanism involving interference with viral reverse transcription as well as transcriptional elongation. Using NMR-based structure determination and molecular modeling tools, I plan to design and subsequently synthesize cyclic peptides with improved binding activity based on the existing already successful peptide leads. It is hypothesized that peptides with improved binding characteristics will also lead to improved anti-viral potency against HIV-1.

Structure based discovery of new inhibitors of HIV replication

245th National Meeting (2013)

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