Α‐Helix‐Mimetic Foldamers for Targeting HIV‐1 TAR RNA. Issue 30 (10th April 2019)

• Record Type: Journal Article
• Authors: Maity, Debabrata; Kumar, Sunil; Curreli, Francesca; Debnath, Asim K.; Hamilton, Andrew D.
• Is Part Of: Chemistry. Volume 25:Issue 30(2019)
• Page Start: 7265
• Page End: 7269
• Publication Date: 2019-04-10
• Subjects: anti-HIV -- foldamers -- oligopyridylamides -- peptidomimetics -- RNA recognition; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201900139
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: An oligopyridylamide‐based foldamer approach has been employed to target HIV TAR RNA‐TAT assembly as a model system to study RNA‐protein interactions. The oligopyridylamide scaffold adopts a constrained conformation which presents surface functionalities at distinct spatial locations and mimic the chemical features of the secondary structure of proteins. We have designed a library of oligopyridylamides containing diverse surface functionalities which mimic the side chain residues of the TAT protein domain. The interaction of TAR RNA and TAT plays a pivotal role in facilitating HIV replication. The library was screened using various fluorescent based assays to identify antagonists of the TAR RNA‐TAT complex. A tricationic oligopyridylamide ADH‐19, possessed the highest affinity towards TAR and efficiently inhibited the TAR RNA‐TAT interaction with apparent K d of 4.1±1.0 μm . Spectroscopic studies demonstrated that ADH‐19 interacts with the bulge and the lower bulge regions of TAR RNA, the domains important for TAT interaction. ADH‐19 demonstrated appreciable in vivo efficacy (IC50 =25±1 μm ) by rescuing TZM‐bl cells infected with the pseudovirus HIV‐1HXB‐2. Abstract : An α‐helical peptidomimetic strategy has been utilized to specifically target HIV TAR RNA and inhibit the TAR RNA‐TAT protein interaction, which is a prerequisite interaction for the proliferation of HIV. The approach can be generalized to target various RNA‐protein interactions which are associated with many diseases.