Abstract
After a long limbo, RNA has gained its credibility as a druggable target, fully earning its deserved role in the next generation of pharmaceutical R&D. We have recently probed the trans-activation response (TAR) element, an RNA stem–bulge–loop domain of the HIV-1 genome with bis-3-chloropiperidines (B-CePs), and revealed the compounds unique behavior in stabilizing TAR structure, thus impairing in vitro the chaperone activity of the HIV-1 nucleocapsid (NC) protein. Seeking to elucidate the determinants of B-CePs inhibition, we have further characterized here their effects on the target TAR and its NC recognition, while developing quantitative analytical approaches for the study of multicomponent RNA-based interactions.
Highlights
The last few years have witnessed a remarkable surge of interest in RNA as a putative therapeutic and research tool, which has led to a greater understanding of structure/function relationships and the discovery of fundamental roles in infection, inflammation, and other disease conditions [1,2]
In this context and to address these needs, we have demonstrated that the concerted application of electrophoretic and mass spectrometry (MS)-based techniques is capable of supporting the characterization of multiple covalent modifications introduced onto RNA by small molecules such as bis-3-chloropiperidines (B-CePs) [8,9]
We leveraged this unique feature to verify the location of guanines involved in long-range quaternary interactions in highly structured RNA systems, such as the kissing loop (KL) complex formed by two copies of the dimerization initiation site (DIS) of the HIV-1 genome [8]
Summary
The last few years have witnessed a remarkable surge of interest in RNA as a putative therapeutic and research tool, which has led to a greater understanding of structure/function relationships and the discovery of fundamental roles in infection, inflammation, and other disease conditions [1,2]. It has become clear that progress in the identification of new inhibitors is severely limited by the dearth of technologies and biophysical tools for the analysis and characterization of the interactions established by RNA, which still lag far behind those available for other types of biopolymers, most notably proteins In this context and to address these needs, we have demonstrated that the concerted application of electrophoretic and mass spectrometry (MS)-based techniques is capable of supporting the characterization of multiple covalent modifications introduced onto RNA by small molecules such as bis-3-chloropiperidines (B-CePs) [8,9]. Follow-up studies aimed at elucidating the determinants of B-CePs activity towards
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