Targeting the HIV RNA Genome: High-Hanging Fruit Only Needs a Longer Ladder

Grice, Stuart F. J. Le

doi:10.1007/82_2015_434

Cited by 27 publications

(32 citation statements)

References 81 publications

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“…Numerous studies have focused on the discovery and design of TAR RNA‐binding inhibitors, including peptides, natural products such as aminoglycosides and synthetic small molecules. These earlier efforts have been summarized in several excellent reviews …”

Section: Viral Rna As a Drug Targetmentioning

confidence: 99%

“…The structured frameshift motif in HIV consists of a long RNA hairpin with an internal loop, which has been explored in ligand targeting approaches that were aimed at stabilizing or disrupting the RNA fold. Earlier studies on the HIV target have been discussed in recent comprehensive reviews by Le Grice, Brakier‐Gingras, and coworkers . In SARS CoV, translation of viral proteins required for replication including the RNA‐dependent RNA polymerase is initiated by a −1 programmed frameshift which is triggered by a three‐stemmed RNA PK (Figure ) …”

Section: Hcv Iresmentioning

confidence: 99%

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Small molecules targeting viral RNA

2016

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Highly conserved noncoding RNA (ncRNA) elements in viral genomes and transcripts offer new opportunities to expand the repertoire of drug targets for the development of antiinfective therapy. Ligands binding to ncRNA architectures are able to affect interactions, structural stability or conformational changes and thereby block processes essential for viral replication. Proof of concept for targeting functional RNA by small molecule inhibitors has been demonstrated for multiple viruses with RNA genomes. Strategies to identify antiviral compounds as inhibitors of ncRNA are increasingly emphasizing consideration of drug-like properties of candidate molecules emerging from screening and ligand design. Recent efforts of antiviral lead discovery for RNA targets have provided drug-like small molecules that inhibit viral replication and include inhibitors of human immunodeficiency virus (HIV), hepatitis C virus (HCV), severe respiratory syndrome coronavirus (SARS CoV), and influenza A virus. While target selectivity remains a challenge for the discovery of useful RNA-binding compounds, a better understanding is emerging of properties that define RNA targets amenable for inhibition by small molecule ligands. Insight from successful approaches of targeting viral ncRNA in HIV, HCV, SARS CoV, and influenza A will provide a basis for the future exploration of RNA targets for therapeutic intervention in other viral pathogens which create urgent, unmet medical needs. Viruses for which targeting ncRNA components in the genome or transcripts may be promising include insect-borne flaviviruses (Dengue, Zika, and West Nile) and filoviruses (Ebola and Marburg). WIREs RNA 2016, 7:726-743. doi: 10.1002/wrna.1373 For further resources related to this article, please visit the WIREs website.

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Section: Viral Rna As a Drug Targetmentioning

confidence: 99%

Section: Hcv Iresmentioning

confidence: 99%

Small molecules targeting viral RNA

2016

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“…Determining the full complement of cis-acting elements in the gRNA that regulate viral replication is necessary for a complete understanding of the HIV-1 replication cycle and may aid in the development of novel antiviral therapies [20]. Furthermore, identifying and characterizing evolutionarily conserved cis-acting elements and structures is essential for understanding HIV-1 purifying and positive selection as well as recombination events [11,12,[21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Increasing the CpG dinucleotide abundance in the HIV-1 genomic RNA inhibits viral replication

et al. 2017

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BackgroundThe human immunodeficiency virus type 1 (HIV-1) structural protein Gag is necessary and sufficient to form viral particles. In addition to encoding the amino acid sequence for Gag, the underlying RNA sequence could encode cis-acting elements or nucleotide biases that are necessary for viral replication. Furthermore, RNA sequences that inhibit viral replication could be suppressed in gag. However, the functional relevance of RNA elements and nucleotide biases that promote or repress HIV-1 replication remain poorly understood.ResultsTo characterize if the RNA sequence in gag controls HIV-1 replication, the matrix (MA) region was codon modified, allowing the RNA sequence to be altered without affecting the protein sequence. Codon modification of nucleotides (nt) 22-261 or 22-378 in gag inhibited viral replication by decreasing genomic RNA (gRNA) abundance, gRNA stability, Gag expression, virion production and infectivity. Comparing the effect of these point mutations to deletions of the same region revealed that the mutations inhibited infectious virus production while the deletions did not. This demonstrated that codon modification introduced inhibitory sequences. There is a much lower than expected frequency of CpG dinucleotides in HIV-1 and codon modification introduced a substantial increase in CpG abundance. To determine if they are necessary for inhibition of HIV-1 replication, codons introducing CpG dinucleotides were mutated back to the wild type codon, which restored efficient Gag expression and infectious virion production. To determine if they are sufficient to inhibit viral replication, CpG dinucleotides were inserted into gag in the absence of other changes. The increased CpG dinucleotide content decreased HIV-1 infectivity and viral replication.ConclusionsThe HIV-1 RNA sequence contains low abundance of CpG dinucleotides. Increasing the abundance of CpG dinucleotides inhibits multiple steps of the viral life cycle, providing a functional explanation for why CpG dinucleotides are suppressed in HIV-1.Electronic supplementary materialThe online version of this article (10.1186/s12977-017-0374-1) contains supplementary material, which is available to authorized users.

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“…11–13 In sum, The central role of TAR in HIV-1 biology underscores its potential as a therapeutic target. 14 Thus, inhibition of the Tat-TAR interaction has been pursued as a potential anti-HIV therapeutic strategy. While numerous classes of small molecules have been reported 15–17 , the lack of anti-HIV drugs targeting TAR in the clinic highlights the challenges in developing small molecule RNA binders.…”

Section: Introductionmentioning

confidence: 99%

Development of Small Molecules with a Noncanonical Binding Mode to HIV-1 Trans Activation Response (TAR) RNA

et al. 2016

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Small molecules that bind to RNA potently and specifically are relatively rare. The study of molecules that bind to the HIV-1 transactivation response (TAR) hairpin, a cis-acting HIV genomic element, has long been an important model system for the chemistry of targeting RNA. Here we report the synthesis, biochemical and structural evaluation of a series of molecules that bind to HIV-1 TAR RNA. A promising analog, 15, retained the TAR binding affinity of the initial hit and displaced a Tat-derived peptide with an IC50 of 40 >M. NMR characterization of a soluble analog, 2, revealed a non-canonical binding mode for this class of compounds. Finally, evaluation of 2 and 15 by Selective 2′-hydroxyl acylation analyzed by primer extension (SHAPE) indicates specificity in binding to TAR within the context of an in vitro-synthesized 365-nt HIV-1 5′-untranslated region (UTR). Thus, these compounds exhibit a novel and specific mode of interaction with TAR, providing important implications for RNA ligand design.

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Targeting the HIV RNA Genome: High-Hanging Fruit Only Needs a Longer Ladder

Cited by 27 publications

References 81 publications

Small molecules targeting viral RNA

Small molecules targeting viral RNA

Increasing the CpG dinucleotide abundance in the HIV-1 genomic RNA inhibits viral replication

Development of Small Molecules with a Noncanonical Binding Mode to HIV-1 Trans Activation Response (TAR) RNA

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