Molecular recognition of a branched peptide with HIV-1 Rev Response Element (RRE) RNA |
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Authors: | Yumin Dai Ashley N. Peralta Jessica E. Wynn Chringma Sherpa Hao Li Astha Verma Stuart F.J. Le Grice Webster L. Santos |
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Affiliation: | 1. Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, United States;2. Basic Research Laboratory, National Cancer Institute, Frederick, MD 21702, United States |
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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. |
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Keywords: | HIV-1 RRE RNA Branched peptides Boronic acids RNA targeting |
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