mRNA Vaccine Sequence and Structure Design and Optimization: Advances and Challenges

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: unknown, P. 108015 - 108015

Published: Nov. 1, 2024

Messenger RNA (mRNA) vaccines have emerged as a powerful tool against communicable diseases and cancers, demonstrated by their huge success during the coronavirus disease 2019 (COVID-19) pandemic. Despite outstanding achievements, mRNA still face challenges such stringent storage requirements, insufficient antigen expression, unexpected immune responses. Since intrinsic properties of molecules significantly impact vaccine performance, optimizing design is crucial in preclinical development. In this review, we outline four key principles for optimal sequence design: enhancing ribosome loading translation efficiency through untranslated region (UTR) optimization, improving via codon increasing structural stability refining global sequence, extending in-cell lifetime expression fidelity adjusting local structures. We also explore recent advancements computational models designing sequences following these principles. By integrating current knowledge, addressing challenges, examining advanced methods, review aims to promote application approaches development inspire novel solutions existing obstacles.

Language: Английский

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Internal cap-initiated translation for efficient protein production from circular mRNA

Nature Biotechnology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

Language: Английский

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Deciphering Phase-Separated Mitochondrial RNA Granules under Stress Conditions with the Mitoribosome-Targeting Small Molecule

Analytical Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

RNA granules are liquid-liquid-phase-separated condensates comprising and proteins. Despite growing insights into their biological functions, studies have predominantly relied on methodologies lacking adequate chemical tools. Here, we introduce ICP-CHARGINGS, a concept for efficiently identifying probes to characterize of interest among nucleic acid-targeting agents. Focusing mitochondrial (MRGs), whose functions remain elusive, developed methodology within this framework identified NATA, new fluorescent molecule that, following mechanistic studies, was found bind the mitoribosome, enabling MRG labeling recognition. Using NATA reveal potential buffering roles MRGs, demonstrated close correlation between maintenance assembly cellular survival proliferation under cold shock hypoxic stress. Overall, introduction implementation ICP-CHARGINGS strategy provide specialized tool advancing our comprehension biology establish paradigm elucidating structures that can be targeted by small molecules, paving way developing tailored diverse in future research.

Language: Английский

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A “Dock-Work” Orange: A Dual-Receptor Biochemical Theory on the Deterrence Induced by Citrusy Aroma on Elephant Traffic Central to a Conservation Effort

Bioinformatics and Biology Insights, Journal Year: 2025, Volume and Issue: 19

Published: Jan. 1, 2025

Conservation of elephants requires physical, chemical, and biological approaches to ensure the protection these gargantuan pachyderms. One such approach is using orange plants (as biofencing) for repellence elephants, which precludes catastrophic events related encroachment into human habitats. Elephants have sensitive olfactory discrimination plant volatile compounds foraging other behavior G-protein-coupled receptors (GPCRs). However, 2 are A2A A2B mediating olfaction elicited by a host ligands, including limonene, main compound in citrus plants, hypothesized be chief repelling agent. Bioinformatics at protein mRNA levels (BLAST/Multiple Sequence Alignments) were employed explore multiple expression products receptors, namely full-length truncated proteins produced isoform mRNAs translated from methionines, while comparison limonene-binding pockets elephant prediction servers [Netphos 3.1; Protter] was used focus, respectively, on contacts limonene binding entails post-translational modifications that involved cell signaling. Finally, link between antifeedant activity explored considering content trees preferentially foraged or avoided as part feeding elephants. The African bush ( Loxodonta africana) possesses receptor but unlike most mammals, expresses highly possessing only transmembrane helices 5, 6, 7. Truncation may lead higher traffic interfaces/pathways aid stronger activation. In addition, all residues putative cleft perfectly conserved both full length truncated. Shallow activation sites require micromolar affinity fewer side-chain interactions, speculated case receptor. An N-terminal extremity N-glycosylation motif indicative membrane localization following accurate folding. A combination truncation, indels, substitutions, transcript isoforms attributed roles evolution L. africana receptor, out receptivity key. It also inferred how act dietary repellent/antifeedant generalist herbivore, with documented being absent some favorites iconic Sclerocarya birrea.

Language: Английский

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Inverted Alu repeats in loop-out exon skipping across hominoid evolution

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 11, 2025

Changes in RNA splicing over the course of evolution have profoundly diversified functional landscape human genome. While DNA sequences proximal to intron-exon junctions are known be critical for splicing, impact distal intronic remains underexplored. Emerging evidence suggests that inverted pairs Alu elements can promote exon skipping by forming stem-loop structures. However, their prevalence and influence throughout remain unknown. Here, we present a systematic analysis across genome assess on through predicted formation relevance hominoid evolution. We found pairs, particularly AluY-AluSx1 AluSz-AluSx, enriched flanking regions skippable exons genome-wide form stable Exons defined weak 3' acceptor strong 5' donor splice sites appear especially prone this mechanism. Through comparative nine primate species, identified 67,126 hominoid-specific insertions, primarily from AluY AluS subfamilies, which genes ubiquitination-related pathways. Experimental validation among several further reinforced potential evolutionary significance. This work extends our current knowledge roles secondary structure formed details newly emerging mechanism transposable contributed genomic innovation at transcriptomic level.

Language: Английский

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Comprehensive benchmarking of large language models for RNA secondary structure prediction

Briefings in Bioinformatics, Journal Year: 2025, Volume and Issue: 26(2)

Published: March 1, 2025

In recent years, inspired by the success of large language models (LLMs) for DNA and proteins, several LLMs RNA have also been developed. These take massive datasets as inputs learn, in a self-supervised way, how to represent each base with semantically rich numerical vector. This is done under hypothesis that obtaining high-quality representations can enhance data-costly downstream tasks, such fundamental secondary structure prediction problem. However, existing RNA-LLM not evaluated this task unified experimental setup. Since they are pretrained models, assessment their generalization capabilities on new structures crucial aspect. Nonetheless, has just partially addressed literature. work we present comprehensive comparative analysis recently proposed. We evaluate use these common deep learning architecture. The were assessed increasing difficulty benchmark datasets. Results showed two clearly outperform other revealed significant challenges low-homology scenarios. Moreover, study provide curated complexity setup scientific endeavor. Source code available repository: https://github.com/sinc-lab/rna-llm-folding/.

Language: Английский

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Reversible Control of RNA Guided Nucleic Acid Cleavage Based on the Inverse Electron Demand Diels‐Alder Reaction^†

Chinese Journal of Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 16, 2025

Comprehensive Summary RNA plays a pivotal role in genetic information transmission, gene expression regulation, and key biological processes, making its functional regulation critical. In this study, we introduce an iedDA‐based strategy for post‐synthetic modification, enabling controlled nucleic acid cleavage via the CRISPR‐Cas system. By modifying with trans ‐cyclooctene (TCO), function is paused, reactivation achieved using repair agent dimethyl‐tetrazine (Me 2 Tz), triggering iedDA reaction. We demonstrate reversible on/off switching of activity vitro further validate strategy's applicability to other systems, highlighting potential editing cells.

Language: Английский

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19F-NMR in RNA structural biology: exploring structures, dynamics, and small molecule interactions

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 117682 - 117682

Published: April 1, 2025

Language: Английский

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Advanced strategies for screening and identifying RNA-targeted small molecules: Bridging therapeutic potential and innovation

Results in Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 102305 - 102305

Published: April 1, 2025

Language: Английский

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RNA-binding motif protein 28 enhances angiogenesis by improving STAT3 translation in hepatocellular carcinoma

Cancer Letters, Journal Year: 2024, Volume and Issue: 604, P. 217191 - 217191

Published: Aug. 23, 2024

Language: Английский

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