Branched peptideboronic acids (BPBAs): a novel mode of binding towards RNA

Zhang, Wenyu; Bryson, David I.; Crumpton, Jason B.; Wynn, Jessica; Santos, Webster L.

doi:10.1039/c3cc00243h

Cited by 31 publications

(35 citation statements)

References 23 publications

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“…Peptide 23 ( Figure 15) was detected to bind to DY547-labeled RRE IIB with a K d value of 1.4 mm. [76] Interestingly, this compound interacts with DNA composed of the same RRE IIB sequence with a much lower affinity (23-fold). The boronic moiety has no negative impact on cellular uptake and compound 23 doesn't reduce cell viability in an MTT assay provided that its concentration is lower than 60 mm.…”

Section: Rev-rre Interactionmentioning

confidence: 99%

The Design of RNA Binders: Targeting the HIV Replication Cycle as a Case Study

et al. 2014

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The human immunodeficiency virus 1 (HIV-1) replication cycle is finely tuned with many important steps involving RNA-RNA or protein-RNA interactions, all of them being potential targets for the development of new antiviral compounds. This cycle can also be considered as a good benchmark for the evaluation of early-stage strategies aiming at designing drugs that bind to RNA, with the possibility to correlate in vitro activities with antiviral properties. In this review, we highlight different approaches developed to interfere with four important steps of the HIV-1 replication cycle: the early stage of reverse transcription, the transactivation of viral transcription, the nuclear export of partially spliced transcripts and the dimerization step.

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Section: Rev-rre Interactionmentioning

confidence: 99%

The Design of RNA Binders: Targeting the HIV Replication Cycle as a Case Study

et al. 2014

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“…65 In this library, two unnatural amino acids containing boronic acid moieties were incorporated: a phenylalanine derivative, F BPA and a benzoyl lysine derivative, K BBA (Figure 8). Installation of boronic acids in biomolecules present a unique mode of interaction due to their ability to form reversible covalent bonds with Lewis bases.…”

Section: Second-generation 334 Branched Peptide Library Targeting Hmentioning

confidence: 99%

“…65a When the boronic acid moiety was removed from K BBA to afford BPBA1.1 , a six-fold decrease of binding affinity towards RRE IIB was observed (Figure 11). In contrast, when an electron withdrawing fluorine atom was installed ortho to the boronic acid group ( BPBA1.2 ), the binding affinity improved to 0.8 μM.…”

Section: Second-generation 334 Branched Peptide Library Targeting Hmentioning

confidence: 99%

HIV-1 drug discovery: targeting folded RNA structures with branched peptides

Wynn

Santos

2015

Org. Biomol. Chem.

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Human immunodeficiency virus type 1 (HIV-1) is an RNA virus that is prone to high rates of mutation. While the disease is managed with current antiretroviral therapies, drugs with a new mode of action are needed. A strategy towards this goal is aimed at targeting the native three-dimensional fold of conserved RNA structures. This perspective highlights medium-sized peptides and peptidomimetics used to target two conserved RNA structures of HIV-1. In particular, branched peptides have the capacity to bind in a multivalent fashion, utilizing a large surface area to achieve the necessary affinity and selectivity toward the target RNA.

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“…These medium-sized branched peptide boronic acids (BPBAs) selectively bound to the tertiary structure of RRE IIB in the low micromolar regime (Table 1), encompassing a large surface area on the RNA. 54, 55 Herein, we report the in vitro activity of these BPBAs via monitoring the expression of HIV-1 p24 capsid protein, as well as HIV-1 replication. One compound, BPBA3 , was shown to inhibit these processes.…”

Section: Introductionmentioning

confidence: 99%

Characterization and in vitro activity of a branched peptide boronic acid that interacts with HIV-1 RRE RNA

Wynn

Zhang

Tebit

et al. 2016

Bioorganic & Medicinal Chemistry

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A branched peptide containing multiple boronic acids was found to bind RRE IIB selectively and inhibit HIV-1 p24 capsid production in a dose-dependent manner. Structure-activity relationship studies revealed that branching in the peptide is crucial for the low micromolar binding towards RRE IIB, and that the peptide demonstrates selectivity towards RRE IIB in the presence of tRNA. Footprinting studies suggest a binding site on the upper stem and internal loop region of the RNA, which induces enzymatic cleavage of the internal loops of RRE IIB upon binding.

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Branched peptideboronic acids (BPBAs): a novel mode of binding towards RNA

Abstract: We report branched peptide boronic acids (BPBAs) that bind to RRE IIB from an on-bead high-throughput screening of a 3.3.4-library (46,656 compounds). We demonstrate that boronic acids are tunable moieties that afford a novel binding mode towards RNA.

Cited by 31 publications

References 23 publications

The Design of RNA Binders: Targeting the HIV Replication Cycle as a Case Study

The Design of RNA Binders: Targeting the HIV Replication Cycle as a Case Study

HIV-1 drug discovery: targeting folded RNA structures with branched peptides

Characterization and in vitro activity of a branched peptide boronic acid that interacts with HIV-1 RRE RNA

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