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

Content Provider	Scilit
Author	Dai, Yumin Peralta, Ashley N. Wynn, Jessica E. Sherpa, Chringma Li, Hao Verma, Astha Grice, Stuart F. J. Le Santos, Webster L.
Copyright Year	2019
Description	Journal: Bioorganic & Medicinal Chemistry 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.
Related Links	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476629/pdf
Ending Page	1765
Page Count	7
Starting Page	1759
ISSN	09680896
e-ISSN	14643391
DOI	10.1016/j.bmc.2019.03.016
Journal	Bioorganic & Medicinal Chemistry
Issue Number	8
Volume Number	27
Language	English
Publisher	Elsevier BV
Publisher Date	2019-03-07
Access Restriction	Open
Subject Keyword	Journal: Bioorganic & Medicinal Chemistry Biochemistry and Molecular Biology Branched Peptides
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Drug Discovery Biochemistry Clinical Biochemistry Molecular Biology Molecular Medicine Pharmaceutical Science