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α‐Helix‐Mimetic Foldamers for Targeting HIV‐1 TAR RNA
Author(s) -
Maity Debabrata,
Kumar Sunil,
Curreli Francesca,
Debnath Asim K.,
Hamilton Andrew D.
Publication year - 2019
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201900139
Subject(s) - rna , tar (computing) , chemistry , protein secondary structure , human immunodeficiency virus (hiv) , biophysics , microbiology and biotechnology , biology , computational biology , biochemistry , virology , gene , computer science , programming language
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 μ m . 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 (IC 50 =25±1 μ m ) by rescuing TZM‐bl cells infected with the pseudovirus HIV‐1HXB‐2.