Molecular recognition of a branched peptide with HIV-1 Rev Response Element (RRE) RNA.
Basic Information
ID: ALA4480452
Journal: Bioorg Med Chem
Title: Molecular recognition of a branched peptide with HIV-1 Rev Response Element (RRE) RNA.
Authors: Dai Y, Peralta AN, Wynn JE, Sherpa C, Li H, Verma A, Le Grice SFJ, Santos WL.
Abstract: Interaction of HIV-1 rev response element (RRE) RNA with its cognate protein, Rev, is critical for HIV-1 replication. Understanding the mode of interaction between RRE RNA and ligands at the binding site can facilitate RNA molecular recognition as well as provide a strategy for developing anti-HIV therapeutics. Our approach utilizes branched peptides as a scaffold for multivalent binding to RRE IIB (high affinity rev binding site) with incorporation of unnatural amino acids to increase affinity via non-canonical interactions with the RNA. Previous high throughput screening of a 46,656-member library revealed several hits that bound RRE IIB RNA in the sub-micromolar range. In particular, the lead compound, 4B3, displayed a Kd value of 410 nM and demonstrated selectivity towards RRE. A ribonuclease protection assay revealed that 4B3 binds to the stem-loop structure of RRE IIB RNA, which was confirmed by SHAPE analysis with 234 nt long NL4-3 RRE RNA. Our studies further indicated interaction of 4B3 with both primary and secondary Rev binding sites.
CiteXplore: 30879859
DOI: 10.1016/j.bmc.2019.03.016
Patent ID: ┄