A Cyclic Mimic of HIV Tat Differentiates Similar TAR RNAs on the Basis of Distinct Dynamic Behaviors.

Abstract:

:Efforts toward the development of RNA-based drug leads have been challenging because of the complexity and dynamic nature of RNA structures as therapeutic targets. The transactivation response (TAR) RNA and cognate Tat protein of HIV have long been recognized as promising antiviral targets, and recent works have identified potentially potent inhibitors of the viral RNA-protein interaction. A new class of such inhibitors, conformationally constrained cyclic peptide mimetics of Tat, has been demonstrated to inhibit the HIV life cycle. We have previously probed the complexity and dynamics of TAR RNAs in their free states, as well as conformational shifting by various peptide and small molecule ligands. In this work, we have used an ultrafast dynamics approach to probe the interactions between TAR RNAs and one of the representatives of cyclic peptide inhibitors, L22. Our studies demonstrated that cyclic L22 specifically recognizes TAR RNAs with a unique single binding site compared to two binding sites for linear Tat protein. Although both Tat and L22 bind to the TAR RNAs as a β-hairpin structure, cyclization in L22 allows it to be a more efficient ligand from a population shifting perspective. This study provided unique insights into drug design with desired properties to differentiate similar structures based on distinct dynamic behaviors.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Lu J,Nguyen L,Zhao L,Xia T,Qi X

doi

10.1021/acs.biochem.5b00325

subject

Has Abstract

pub_date

2015-06-16 00:00:00

pages

3687-93

issue

23

eissn

0006-2960

issn

1520-4995

journal_volume

54

pub_type

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