While human immunodeficiency virus type 1 (HIV-1) is manageable with current antiretroviral therapies, the majority of FDA approved drugs for HIV-1 target enzymes that are prone to high rates of mutation. This leads to drug resistance over time and hence alternative therapy with a new mode of action is urgently needed. Our research focuses on targeting a conserved region of the HIV-1 genome, the rev response element (RRE) RNA; interaction of this RNA with its cognate protein Rev is critical for HIV-1 replication. Therefore, disruption of this interaction is a viable strategy for developing anti-HIV therapeutics. Our approach utilizes branched peptides as a scaffold for multivalent binding to RRE IIB (high affinity binding site), with the incorporation of unnatural amino acids to increase binding affinity via non-canonical interactions with the RNA. High-throughput screening of a 3.3.4 branched peptide boronic acid (BPBA) library revealed hits that selectively bound to RRE IIB RNA in the submicromolar range. Incorporation of acridine into a subsequent 3.3.4 BPBA library afforded hits in the low nanomolar range, suggesting that as an intercalating agent acridine boosted affinity towards the RNA target. Our current library utilizes all unnatural amino acids at each variable position to facilitate binding to RNA through potential hydrogen and reversible covalent bonding, pi stacking, and electrostatic interactions. Synthesis and high-throughput screening of this library will be discussed, including the deconvolution and biophysical characterizations of hit branched peptides.

"Rev"olutionary library containing unnatural amino acids: Functionalizing branched peptides toward targeting folded RNA structures

250th National Meeting (2015)

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