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Molecular recognition of a branched peptide with HIV-1 Rev Response Element (RRE) RNA.
- Source :
-
Bioorganic & Medicinal Chemistry . Apr2019, Vol. 27 Issue 8, p1759-1765. 7p. - Publication Year :
- 2019
-
Abstract
- Graphical abstract 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 K d 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *RNA
*MOLECULAR recognition
*BINDING sites
*LEAD compounds
Subjects
Details
- Language :
- English
- ISSN :
- 09680896
- Volume :
- 27
- Issue :
- 8
- Database :
- Academic Search Index
- Journal :
- Bioorganic & Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 135492560
- Full Text :
- https://doi.org/10.1016/j.bmc.2019.03.016