Discovering riboswitches: the past and the future

Kumari, Kavita; Breaker, Ronald R.

doi:10.1016/j.tibs.2022.08.009

Cited by 109 publications

(94 citation statements)

References 212 publications

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“…We wrote custom descriptors for the deoxyguanosine, adenine, and guanine riboswitches, as well as the HDV, hammerhead, and twister ribozymes (Kingsford et al 2007;Eddy 2012). One could, of course, include descriptors for a much wider range of RNA motifs, such as hairpins, ribozymes, and riboswitches (Bevilacqua and Blose 2008;Campillos et al 2010;Mccown et al 2017;Kavita and Breaker 2022). After validating our RNABOB descriptors on a set of positive and negative control RNAs, we scanned the SARS-CoV-2 genome for these motifs.…”

Section: Development and Optimization Of The Pseudoknot (Pk) Modulementioning

confidence: 99%

The Functional RNA Identification (FRID) Pipeline: Identification of Potential Pseudoknot-Containing RNA Elements as Therapeutic Targets for SARS-CoV-2

Forstmeier

Meyer

Bevilacqua

2023

Preprint

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The COVID-19 pandemic persists despite the development of effective vaccines. As such, it remains crucial to identify new targets for antiviral therapies. The causative virus of COVID-19, SARS-CoV-2, is a positive-sense RNA virus with RNA structures that could serve as therapeutic targets. One such RNA with established function is the frameshift stimulatory element (FSE), which promotes programmed ribosomal frameshifting. To accelerate identification of additional functional RNA elements, we introduce a novel computational approach termed the Functional RNA Identification (FRID) pipeline. The guiding principle of our pipeline, which uses established component programs as well as customized component programs, is that functional RNA elements have conserved secondary and pseudoknot structures that facilitate function. To assess the presence and conservation of putative functional RNA elements in SARS-CoV-2, we compared over 6,000 SARS-CoV-2 genomic isolates. We identified 22 functional RNA elements from the SARS-CoV-2 genome, 14 of which have conserved pseudoknots and serve as potential targets for small molecule or antisense oligonucleotide therapeutics. The FRID pipeline is general and can be applied to identify pseudoknotted RNAs for targeted therapeutics in genomes or transcriptomes from any virus or organism.

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Section: Development and Optimization Of The Pseudoknot (Pk) Modulementioning

confidence: 99%

The Functional RNA Identification (FRID) Pipeline: Identification of Potential Pseudoknot-Containing RNA Elements as Therapeutic Targets for SARS-CoV-2

Forstmeier

Meyer

Bevilacqua

2023

Preprint

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“…Such structural variety provides disparate RNA molecules with catalytic properties needed for life (ribozymes), the ability to sense and react to changes in the environment (riboswitches), the capacity to bind to other RNA molecules and organize complex structures (such as seen with long non-coding RNA), and the ability to self-replicate (RNA polymerase ribozymes). 3 …”

Section: The Rna Worldmentioning

confidence: 99%

Future Impact of mRNA Therapy on Cardiovascular Diseases

Cooke¹,

Youker

2022

Methodist DeBakey Cardiovascular Journal

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The silver lining of the recent pandemic was that it accelerated the emergence of messenger ribonucleic acid (mRNA) therapeutics. The great promise of mRNA therapeutics was highlighted by the speed at which the vaccines were created, tested, and proven to be relatively safe and highly effective. There are a wide variety of mRNA therapeutics now under development, and dozens of these are in clinical trials. These therapeutics are generating a major paradigm shift in medical therapy, including the treatment of cardiovascular disease. Most of the cardiovascular mRNA therapies are still in preclinical development, although a phase 2a trial of mRNA therapy for myocardial ischemia has been completed with promising results. 1 The application of mRNA therapies to cardiovascular diseases is virtually limitless, and ongoing work includes mRNA therapies for myocardial ischemia, heart failure, arrhythmias, hypercholesterolemia, and arterial occlusive diseases. In addition, mRNA may be used to enhance cell therapies. In the future, mRNA therapies for cardiovascular disease are destined to supplant some of our current biologics and pharmacotherapies and will be used to treat previously untreatable cardiovascular diseases. Furthermore, mRNA therapies can be personalized, and they can be rapidly generated in current Good Manufacturing Practice facilities with a modest footprint, facilitating the rise of hospital-based regional centers of RNA therapeutics.

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“…Perhaps no system better demonstrates specific and high-affinity RNA small-molecule interactions that drive a biological outcome than riboswitches. Riboswitches are non-coding RNA elements typically found in the 5′-leader of messenger RNAs (mRNAs), mostly in bacteria . Small molecule binding to the riboswitch regulates the expression of mRNA by directing the formation of alternative RNA structures that inform the expression machinery.…”

Section: Introductionmentioning

confidence: 99%

Targeting Riboswitches with Beta-Axial-Substituted Cobalamins

et al. 2023

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RNA-targeting small-molecule therapeutics is an emerging field hindered by an incomplete understanding of the basic principles governing RNA–ligand interactions. One way to advance our knowledge in this area is to study model systems where these interactions are better understood, such as riboswitches. Riboswitches bind a wide array of small molecules with high affinity and selectivity, providing a wealth of information on how RNA recognizes ligands through diverse structures. The cobalamin-sensing riboswitch is a particularly useful model system, as similar sequences show highly specialized binding preferences for different biological forms of cobalamin. This riboswitch is also widely dispersed across bacteria and therefore holds strong potential as an antibiotic target. Many synthetic cobalamin forms have been developed for various purposes including therapeutics, but their interaction with cobalamin riboswitches is yet to be explored. In this study, we characterize the interactions of 11 cobalamin derivatives with three representative cobalamin riboswitches using in vitro binding experiments (both chemical footprinting and a fluorescence-based assay) and a cell-based reporter assay. The derivatives show productive interactions with two of the three riboswitches, demonstrating simultaneous plasticity and selectivity within these RNAs. The observed plasticity is partially achieved through a novel structural rearrangement within the ligand binding pocket, providing insight into how similar RNA structures can be targeted. As the derivatives also show in vivo functionality, they serve as several potential lead compounds for further drug development.

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Discovering riboswitches: the past and the future

Cited by 109 publications

References 212 publications

The Functional RNA Identification (FRID) Pipeline: Identification of Potential Pseudoknot-Containing RNA Elements as Therapeutic Targets for SARS-CoV-2

The Functional RNA Identification (FRID) Pipeline: Identification of Potential Pseudoknot-Containing RNA Elements as Therapeutic Targets for SARS-CoV-2

Future Impact of mRNA Therapy on Cardiovascular Diseases

Targeting Riboswitches with Beta-Axial-Substituted Cobalamins

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