Molecular recognition of a branched peptide with HIV-1 Rev Response Element (RRE) RNA

Bioorg Med Chem. 2019 Apr 15;27(8):1759-1765. doi: 10.1016/j.bmc.2019.03.016. Epub 2019 Mar 7.

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.

Keywords: Boronic acids; Branched peptides; HIV-1; RNA targeting; RRE RNA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Binding Sites
  • HIV-1 / genetics*
  • Humans
  • Nucleic Acid Conformation
  • Peptides / chemical synthesis
  • Peptides / chemistry*
  • Peptides / metabolism
  • Protein Binding
  • RNA, Viral / chemistry*
  • RNA, Viral / metabolism
  • Response Elements / genetics*
  • Ribonucleases / chemistry
  • Ribonucleases / metabolism

Substances

  • Peptides
  • RNA, Viral
  • Ribonucleases