Nucleic acid recognition and antiviral activity of 1,4-substituted terphenyl compounds mimicking all faces of the HIV-1 Rev protein positively-charged α-helix

Abstract

Small synthetic molecules mimicking the three-dimensional structure of α-helices may find applications as inhibitors of therapeutically relevant protein-protein and protein-nucleic acid interactions. However, the design and use of multi-facial helix mimetics remains in its infancy. Here we describe the synthesis and application of novel bilaterally substituted p-terphenyl compounds containing positively-charged aminoalkyl groups in relative 1,4 positions across the aromatic scaffold. These compounds were specifically designed to mimic all faces of the arginine-rich α-helix of the HIV-1 protein Rev, which forms deeply embedded RNA complexes and plays key roles in the virus replication cycle. Two of these molecules recognized the Rev site in the viral RNA and inhibited the formation of the RRE-Rev ribonucleoprotein complex, a currently unexploited target in HIV chemotherapy. Cellular assays revealed that the most active compounds blocked HIV-1 replication with little toxicity, and likely exerted this effect through a multi-target mechanism involving inhibition of viral LTR promoterdependent transcription and Rev function. Further development of this scaffold may open new avenues for targeting nucleic acids and may complement current HIV therapies, none of which involve inhibitors interfering with the gene regulation processes of the virus.Protein α-helices are often involved in interactions with DNA, RNA or other proteins 1 . These complexes regulate many important biological processes, but are widely considered difficult targets for drug development. In this context, there has been a strong interest in developing synthetic small molecules that mimic the topology of α-helices, as this would facilitate the drug discovery process while potentially overcoming the pharmacokinetic limitations often encountered when using peptides as drugs 2-4 . Hamilton et al. pioneered this field by reporting that tris-substituted 3,2′,2″-terphenyl molecules reproduced the angular orientation of side chains i, i + 4 and i + 7 of an α-helix, and were capable of blocking protein-protein interactions 5,6 . However, Hamilton's design was restricted to terphenyls substituted on one side of the molecule, mimicking just one face of an α-helix and limiting the possible therapeutic applications to superficial protein-protein interactions. We recently reported that terphenyl molecules with bilateral 3,5, 2′,6′,2″,6″ substitutions adopted a staggered conformation that matched the projection of side chains i, i + 1. i + 4, i + 5, i + 7 and i + 8, thereby mimicking all three faces of an α-helix Inhibition of the RRE-Rev interaction. Molecular modelling calculations indicated that 1,4-terphenyl molecules could approximately match side chains i, i + 2, i + 4, i + 6, i + 7 and i + 9 of an α-helix (Fig. 1B). When applied to the Rev 34-50 α-helix, the side chains of our terphenyl compounds were found to coincide with Rev residues reported to be essential for the interaction with subdomain IIB (Fig. S2).We first evaluated whether 1,4-terphenyl molecules ...

HibeRNAtion: HIV-1 RNA Metabolism and Viral Latency

“…The same group subsequently described another compound, benzofluorenone or Benfluron, that targets Rev-RRE binding by binding to the RRE and inhibits viral gene expression ( Prado et al., 2018 ). Recently, a drug discovery study reported the design of the multi-target small molecule 1,4-substituted terphenyl compounds that inhibit HIV-1 transcription and Rev-dependent export by binding to the RRE element ( Medina-Trillo et al., 2020 ). Nevertheless, while some of these drugs are very effective and sensitive, the relative specificity and possible secondary binding targets (i.e.…”

Taxonomic Characterization, Antiviral Activity and Induction of Three New Kenalactams in Nocardiopsis sp. CG3

“…Moreover, the class of terphenyl compounds, which include the p-terphenyl derivative 6 detected in F2 (Fig. 4 ), can exert an antiviral activity [ 51 ]. However, mitomycin C detected in F2 is not known to have antiviral activity.…”

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“…Considering this complexity, comprehensive studies of these factors are necessary for effective intervention, including the elucidation of viral counteractors. Encouragingly, several druggable PT inhibitors have already been reported to be effective in suppressing HIV-1 in vitro or ex vivo [127][128][129][130][131][132]. Thus, the pursuit of PT latency control emerges as a pivotal strategy in combating HIV-1 latency, warranting further careful investigation on its intricacies.…”