Simultaneous recognition of HIV-1 TAR RNA bulge and loop sequences by cyclic peptide mimics of Tat protein

Journal Article · Tue Jul 21 04:00:00 EDT 2009 · Proceedings of the National Academy of Sciences of the United States of America, 106(29):11931-11936

DOI:https://doi.org/10.1073/pnas.0900629106· OSTI ID:965535

Davidson, Amy; Leeper, Thomas C; Athanassiou, Zafiria; Patora-Komisarska, Krystyna; Karn, Jonathan; Robinson, John A; Varani, Gabriele

The interaction of the HIV-1 transactivator protein Tat with its transactivation response (TAR) RNA is an essential step in viral replication and therefore an attractive target for developing antivirals with new mechanisms of action. Numerous compounds that bind to the 3-nt bulge responsible for binding Tat have been identified in the past, but none of these molecules had sufficient potency to warrant pharmaceutical development. We have discovered conformationally-constrained cyclic peptide mimetics of Tat that are specific nM inhibitors of the Tat-TAR interaction by using a structure-based approach. The lead peptides are nearly as active as the antiviral drug nevirapine against a variety of clinical isolates in human lymphocytes. The NMR structure of a peptide–RNA complex reveals that these molecules interfere with the recruitment to TAR of both Tat and the essential cellular cofactor transcription elongation factor-b (P-TEFb) by binding simultaneously at the RNA bulge and apical loop, forming an unusually deep pocket. This structure illustrates additional principles in RNA recognition: RNA-binding molecules can achieve specificity by interacting simultaneously with multiple secondary structure elements and by inducing the formation of deep binding pockets in their targets. It also provides insight into the P-TEFb binding site and a rational basis for optimizing the promising antiviral activity observed for these cyclic peptides.

• Research Organization: Pacific Northwest National Laboratory (PNNL), Richland, WA (US), Environmental Molecular Sciences Laboratory (EMSL)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC05-76RL01830
• OSTI ID: 965535
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America, 106(29):11931-11936, Journal Name: Proceedings of the National Academy of Sciences of the United States of America, 106(29):11931-11936 Journal Issue: 29 Vol. 106; ISSN PNASA6; ISSN 0027-8424
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
DRUGS
ELONGATION
Environmental Molecular Sciences Laboratory
LYMPHOCYTES
PEPTIDES
PROTEINS
RNA
SPECIFICITY
TAR
TARGETS
TRANSCRIPTION