Small Drugs, Huge Impact: The Extraordinary Impact of Antisense Oligonucleotides in Research and Drug Development

Molecules, Journal Year: 2022, Volume and Issue: 27(2), P. 536 - 536

Published: Jan. 15, 2022

Antisense oligonucleotides (ASOs) are an increasingly represented class of drugs. These small sequences nucleotides designed to precisely target other oligonucleotides, usually RNA species, and modified protect them from degradation by nucleases. Their specificity is due their sequence, so it possible any sequence that already known. molecules very versatile adaptable given chemistry can be custom manufactured. Based on the being used, activity may significantly change effects cell function phenotypes differ dramatically. While some will cause decay, others only bind act as a steric blocker. incredible versatility key manipulating several aspects nucleic acid well process, alter transcriptome profile specific type or tissue. For example, they used modify splicing mask sites target. The entire design rather than just essential ensuring ASO its Thus, vitally important ensure complete process drug testing taken into account. ASOs’ adaptability considerable advantage, over past decades has allowed multiple new drugs approved. This, in turn, had significant positive impact patient lives. Given current challenges presented COVID-19 pandemic, necessary find therapeutic strategies would complement vaccination efforts across globe. ASOs powerful tool virus provide paradigm. proof efficacy anti-viral agent long-standing, yet no molecule currently FDA approval. emergence widespread use vaccines during this health crisis might ideal opportunity develop first market. In review, we describe story ASOs, different characteristics chemistry, how translate research clinical tool.

Language: Английский

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The key features of SARS-CoV-2 leader and NSP1 required for viral escape of NSP1-mediated repression

RNA, Journal Year: 2022, Volume and Issue: 28(5), P. 766 - 779

Published: March 1, 2022

SARS-CoV-2, responsible for the ongoing global pandemic, must overcome a conundrum faced by all viruses. To achieve its own replication and spread, it simultaneously depends on subverts cellular mechanisms. At early stage of infection, SARS-CoV-2 expresses viral nonstructural protein 1 (NSP1), which inhibits host translation blocking mRNA entry tunnel ribosome; this interferes with binding mRNAs to ribosome. Viral mRNAs, other hand, blockade. We show that NSP1 enhances expression containing leader. The first stem-loop (SL1) in leader is both necessary sufficient enhancement mechanism. Our analysis pinpoints specific residues within SL1 (three cytosine at positions 15, 19, 20) another (R124), are required evasion, thus might present promising drug targets. target antisense oligo (ASO) efficiently specifically down-regulate mRNA. Additionally, we carried out functional interactome using BioID identified components antiviral defense pathways. therefore suggests mechanism genes while enhancing RNA. This helps reconcile conflicting reports literature regarding mechanisms virus avoids silencing.

Language: Английский

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Divalent siRNAs are bioavailable in the lung and efficiently block SARS-CoV-2 infection

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(11)

Published: March 9, 2023

The continuous evolution of SARS-CoV-2 variants complicates efforts to combat the ongoing pandemic, underscoring need for a dynamic platform rapid development pan-viral variant therapeutics. Oligonucleotide therapeutics are enhancing treatment numerous diseases with unprecedented potency, duration effect, and safety. Through systematic screening hundreds oligonucleotide sequences, we identified fully chemically stabilized siRNAs ASOs that target regions genome conserved in all concern, including delta omicron. We successively evaluated candidates cellular reporter assays, followed by viral inhibition cell culture, eventual testing leads vivo antiviral activity lung. Previous attempts deliver therapeutic oligonucleotides lung have met only modest success. Here, report identifying generating potent, modified multimeric bioavailable after local intranasal intratracheal delivery. optimized divalent showed robust human cells mouse models infection represent new paradigm current future pandemics.

Language: Английский

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Preparing for the next viral threat with broad-spectrum antivirals

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(11)

Published: May 31, 2023

There is a large global unmet need for the development of countermeasures to combat hundreds viruses known cause human disease and establishment therapeutic portfolio future pandemic preparedness. Most approved antiviral therapeutics target proteins encoded by single virus, providing narrow spectrum coverage. This, combined with slow pace high cost drug development, limits scalability this direct-acting (DAA) approach. Here, we summarize progress challenges in broad-spectrum antivirals that either viral elements (proteins, genome structures, lipid envelopes) or cellular proviral factors co-opted multiple via newly discovered compounds repurposing drugs. These strategies offer new means developing against both existing emerging threats complement DAAs.

Language: Английский

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Antiviral Therapy of COVID-19

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(10), P. 8867 - 8867

Published: May 16, 2023

Since the beginning of COVID-19 pandemic, scientific community has focused on prophylactic vaccine development. In parallel, experience pharmacotherapy this disease increased. Due to declining protective capacity vaccines against new strains, as well increased knowledge about structure and biology pathogen, control shifted focus antiviral drug development over past year. Clinical data safety efficacy antivirals acting at various stages virus life cycle been published. review, we summarize mechanisms clinical therapy with drugs based plasma convalescents, monoclonal antibodies, interferons, fusion inhibitors, nucleoside analogs, protease inhibitors. The current status described is also summarized in relation official guidelines for treatment COVID-19. addition, here describe innovative whose effect provided by antisense oligonucleotides targeting SARS-CoV-2 genome. Analysis laboratory suggests that successfully combat broad spectra emerging strains providing reliable defense

Language: Английский

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MiRNA-SARS-CoV-2 dialogue and prospective anti-COVID-19 therapies

Life Sciences, Journal Year: 2022, Volume and Issue: 305, P. 120761 - 120761

Published: July 2, 2022

Language: Английский

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Structural and Functional RNA Motifs of SARS-CoV-2 and Influenza A Virus as a Target of Viral Inhibitors

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(2), P. 1232 - 1232

Published: Jan. 8, 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic, whereas influenza A virus (IAV) causes seasonal epidemics and occasional pandemics. Both viruses lead to widespread infection death. SARS-CoV-2 are RNA viruses. The genome an approximately 30 kb, positive sense, 5′ capped single-stranded molecule. possesses eight negative-sense segments. secondary structure in untranslated coding regions crucial viral replication cycle. within of has been intensively studied. Because whole cycles dependent on with no DNA intermediate, a natural promising target development inhibitors. There lot RNA-targeting strategies regulating pathogenic RNA, such as small interfering interference, antisense oligonucleotides, catalytic nucleic acids, molecules. In this review, we summarized knowledge about inhibition propagation by targeting their structure.

Language: Английский

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Early alveolar epithelial cell necrosis is a potential driver of COVID-19-induced acute respiratory distress syndrome

iScience, Journal Year: 2022, Volume and Issue: 26(1), P. 105748 - 105748

Published: Dec. 6, 2022

Acute respiratory distress syndrome (ARDS) with COVID-19 is aggravated by hyperinflammatory responses even after the peak of viral load has passed; however, its underlying mechanisms remain unclear. In present study, analysis alveolar tissue injury markers and epithelial cell death in patients revealed that COVID-19-induced ARDS was characterized necrosis at an early disease stage. Serum levels HMGB-1, one DAMPs released from necrotic cells, were also significantly elevated these patients. Further using a mouse model mimicking showed involved two forms programmed necrosis, namely necroptosis, pyroptosis. Finally, neutralization HMGB-1 attenuated model. Collectively, including necroptosis pyroptosis, predominant form stage subsequent release potential driver ARDS.

Language: Английский

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Antisense oligonucleotides to therapeutically target SARS-CoV-2 infection

PLoS ONE, Journal Year: 2023, Volume and Issue: 18(2), P. e0281281 - e0281281

Published: Feb. 3, 2023

Although the COVID-19 pandemic began over three years ago, virus responsible for disease, SARS-CoV-2, continues to infect people across globe. As such, there remains a critical need development of novel therapeutics against SARS-CoV-2. One technology that has remained relatively unexplored in is use antisense oligonucleotides (ASOs)—short single-stranded nucleic acids bind target RNA transcripts modulate their expression. In this study, ASOs targeted SARS-CoV-2 genome and host entry factors, ACE2 TMPRSS2 , were designed tested ability inhibit cellular infection by Using our previously developed bioassay platform, we screened 180 total targeting various regions validated several potently blocked vitro . Notably, select retained activity both WA1 B.1.1.7 (commonly known as alpha) variants. Screening showed also prevented viruses cell lines. Combined with demonstrated success other disease indications, these results support further research into factors potential therapeutics.

Language: Английский

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High-resolution structure of stem-loop 4 from the 5′-UTR of SARS-CoV-2 solved by solution state NMR

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 51(20), P. 11318 - 11331

Published: Oct. 4, 2023

We present the high-resolution structure of stem-loop 4 5'-untranslated region (5_SL4) severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) genome solved by solution state nuclear magnetic resonance spectroscopy. 5_SL4 adopts an extended rod-like with a single flexible looped-out nucleotide and two mixed tandem mismatches, each composed G•U wobble base pair pyrimidine•pyrimidine mismatch, which are incorporated into structure. Both mismatches residue destabilize locally. Their distribution along suggests role these non-canonical elements in retaining functionally important structural plasticity particular regard to accessibility start codon upstream open reading frame located RNA's apical loop. The loop-although mostly flexible-harbors residual features suggesting additional molecular recognition processes. is highly conserved among different variants SARS-CoV-2 can be targeted small molecule ligands, it binds intermediate affinity vicinity within

Language: Английский

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