Causes, functions, and therapeutic possibilities of RNA secondary structure ensembles and alternative states

Cell chemical biology, Год журнала: 2024, Номер 31(1), С. 17 - 35

Опубликована: Янв. 1, 2024

Язык: Английский

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RNATACs: Multispecific small molecules targeting RNA by induced proximity

Cell chemical biology, Год журнала: 2024, Номер 31(6), С. 1101 - 1117

Опубликована: Июнь 1, 2024

RNA-targeting small molecules (rSMs) have become an attractive modality to tackle traditionally undruggable proteins and expand the druggable space. Among many innovative concepts, chimeras (RNATACs) represent a new class of multispecific, induced proximity that act by chemically bringing RNA targets into with endogenous effector, such as ribonuclease (RNase). Depending on RNATACs can alter stability, localization, translation, or splicing target RNA. Although still in its infancy, this has potential for broad applications future treat diseases high unmet need. In review, we discuss advantages RNATACs, recent progress field, challenges cutting-edge technology.

Язык: Английский

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Small Molecules Targeting Viral RNA

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(17), С. 13500 - 13500

Опубликована: Авг. 31, 2023

The majority of antivirals available target viral proteins; however, RNA is emerging as a new and promising antiviral due to the presence highly structured in genomes fundamental for their replication cycle. Here, we discuss methods identification RNA-targeting compounds, starting from determination structures either purified or living cells, followed by silico screening on phenotypic assays evaluate inhibition. Moreover, review small molecules known programmed ribosomal frameshifting element SARS-CoV-2, internal entry site different viruses, elements HIV.

Язык: Английский

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A Cascade of Conformational Switches in SARS-CoV-2 Frameshifting: Coregulation by Upstream and Downstream Elements

Biochemistry, Год журнала: 2025, Номер unknown

Опубликована: Фев. 5, 2025

Targeting ribosomal frameshifting has emerged as a potential therapeutic intervention strategy against COVID-19. In this process, −1 shift in the reading frame encodes alternative viral proteins. Any interference with process profoundly affects replication and propagation. For SARS-CoV-2, two RNA sites associated are positioned on 5′ 3′ of residues. Although much attention been focused frameshift element (FSE), stem-loop (attenuator hairpin, AH) can play role. Yet relationship between regions is unknown. addition, multiple folds FSE FSE-containing have discovered. To gain more insight into these larger sequence context that includes AH, we apply our graph-theory-based modeling tools to represent secondary structures, "RAG" (RNA-As-Graphs), generate conformational landscapes suggest length-dependent distributions. We show AH region coexist main 3-stem pseudoknots (dual graphs 3_6 3_3 notation) but an stem 1 (AS1) disrupt trigger other folds. A critical length for AS1 10-bp regulates key folding transitions. Together designed mutants available experimental data, present sequential view during their mechanistic roles. These structural mutational insights both ends advance understanding SARS-CoV-2 mechanism by suggesting how role defining techniques target specific

Язык: Английский

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Synthesis and evolution of 16-membered macrolide carrimycin derivatives as a novel class of anti-HCoV-OC43 agents targeting viral FSE RNA

European Journal of Medicinal Chemistry, Год журнала: 2025, Номер 287, С. 117373 - 117373

Опубликована: Фев. 7, 2025

Язык: Английский

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RNA modulation

Elsevier eBooks, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

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Structural switching dynamically controls the doubly pseudoknotted Rous sarcoma virus–programmed ribosomal frameshifting element

Proceedings of the National Academy of Sciences, Год журнала: 2025, Номер 122(14)

Опубликована: Апрель 2, 2025

A hallmark of retrovirus replication is the translation two different polyproteins from one RNA through programmed –1 frameshifting. This a mechanism in which actively translating ribosome induced to slip 5′ direction at defined codon and then continues new reading frame. Programmed frameshifting controls stoichiometry viral proteins therefore under stringent evolutionary selection. Forty years ago, first stimulatory element was discovered Rous sarcoma virus. The ~120 nt segment predicted contain pseudoknot, but its 3D structure has remained elusive. Now, we have determined cryoEM X-ray crystallographic structures this classic retroviral element, finding that it adopts butterfly-like double-pseudoknot fold. One “wing” contains dynamic pyrimidine-rich helix, observed crystallographically conformations third conformation via cryoEM. other wing encompasses interacts with second unexpected pseudoknot toggle residue, A2546. key purine switches between structural states tunes stability interacting residues wings. We find mutation can modulate by as much 50-fold, likely altering relative abundance conformational ensemble RNA. Taken together, our structure–function analyses reveal how double junction stimulates taking advantage heterogeneity, supporting multistate model high Shannon entropy enhances efficiency.

Язык: Английский

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An intricate balancing act: Upstream and downstream frameshift co-regulatory elements

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 27, 2024

Abstract Targeting ribosomal frameshifting has emerged as a potential therapeutic intervention strategy against Covid-19. During translation, fraction of elongating ribosomes slips by one base in the 5 ′ direction and enters new reading frame for viral protein synthesis. Any interference with this process profoundly affects replication propagation. For Covid-19, two RNA sites associated SARS-CoV-2 are positioned on 3 residues. Although much attention been frameshift element (FSE), stem-loop (attenuator hairpin, AH) can play role. The formation AH suggested to occur refolding structure is triggered unwinding. However, attenuation activity relationship between regions unknown. To gain more insight into these related RNAs further enrich our understanding SARS-CoV-2, we explore folding both frameshifting. Using graph-theory-based modeling tools represent secondary structures, “RAG” (RNA-As-Graphs), conformational landscapes analyze length-dependent distributions, show that coexists 3-stem pseudoknot FSE (graph 3_6 dual graph notation) alternative 3_3) but less likely other folds (such 3-way junction 3_5). This because an Stem 1 (AS1) disrupt pseudoknots trigger folds. In addition, design four mutants long lengths stabilize or AH, AS1 illustrate deduced AH/AS1 roles favor 3_5, stem-loop. These how strengthened result from weakened AS1, while dominant occurs AS1. structural mutational insights ends advance mechanism suggesting sequence folds, which turn define techniques involving elements. Our work also highlights complexity challenges analyzing multiple conformations.

Язык: Английский

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Targeting RNA with small molecules, from RNA structures to precision medicines: IUPHAR review: 40

British Journal of Pharmacology, Год журнала: 2024, Номер 181(21), С. 4152 - 4173

Опубликована: Сен. 3, 2024

RNA plays important roles in regulating both health and disease biology all kingdoms of life. Notably, can form intricate three‐dimensional structures, their biological functions are dependent on these structures. Targeting the structured regions with small molecules has gained increasing attention over past decade, because it provides chemical probes to study fundamental processes lead medicines for diseases unmet medical needs. Recent advances structure prediction determination have accelerated rational design development RNA‐targeted modulate pathology. However, challenges remain advancing towards clinical applications. This review summarizes strategies identify recognizing augment functionality RNA‐binding molecules. We focus recent developing as potential therapeutics a variety diseases, encompassing different modes actions targeting strategies. Furthermore, we present current gaps between early‐stage discovery applications, well roadmap overcome near future.

Язык: Английский

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Cyclic peptides targeting the SARS-CoV-2 programmed ribosomal frameshifting RNA from a multiplexed phage display library

Опубликована: Май 8, 2024

RNA provides the genetic blueprint for many pathogenic viruses, including SARS-CoV-2. The propensity of to fold into specific tertiary structures enables biomolecular recognition cavities and crevices suited binding drug-like molecules. Despite increasing interest in as a target chemical biology therapeutic applications, development molecules that recognize with high affinity specificity represents significant challenge. Here, we report strategy discovery selection RNA-targeted macrocyclic peptides derived from combinatorial libraries peptide macrocycles displayed by bacteriophages. Specifically, platform phage display organo-peptide hybrids (MOrPH-PhD) was combined diverse set non-canonical amino acid-based cyclization modules produce large 10^7 structurally diverse, genetically encoded macrocycles. These were panned against -1 programmed ribosomal frameshifting stimulatory sequence (FSS) pseudoknot SARS-CoV-2, which revealed sequences bind this essential motif selectivity. Peptide localizes FSS dimerization loop based on modification analysis assays. This work introduces novel system generation high-throughput screening topologically cyclopeptide scaffolds (multiplexed MOrPH-PhD), it exploration evolution RNAs.

Язык: Английский

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