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

被引:145
作者
Davidson, Amy [1 ]
Leeper, Thomas C. [1 ]
Athanassiou, Zafiria [1 ]
Patora-Komisarska, Krystyna [2 ]
Karn, Jonathan [3 ]
Robinson, John A. [2 ]
Varani, Gabriele [1 ,4 ]
机构
[1] Univ Washington, Dept Chem, Seattle, WA 98195 USA
[2] Univ Zurich, Inst Organ Chem, CH-8057 Zurich, Switzerland
[3] Case Western Reserve Univ, Dept Mol Biol & Microbiol, Cleveland, OH 44106 USA
[4] Univ Washington, Dept Biochem, Seattle, WA 98195 USA
基金
美国国家卫生研究院;
关键词
NMR; transcription elongation factor-b; antiviral; Tat-TAR interaction; RNA recognition; GENE-EXPRESSION; SMALL-MOLECULE; HIGH-AFFINITY; DESIGN; CONFORMATION; DRUG; INHIBITORS; LIGANDS; BINDING;
D O I
10.1073/pnas.0900629106
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:11931 / 11936
页数:6
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