Identification of Novel Targets for Enhancing Targeted RNA Degradation in Antiviral Discovery
NIAID - National Institute of Allergy and Infectious Diseases
About This Grant
PROJECT SUMMARY / ABSTRACT The development of targeted RNA degradation (TRD) technologies, such as RNA-degrading chimeras, holds significant promise for antiviral therapies by reducing viral RNA levels to prevent viral replication. Despite their potential, current TRD mechanisms exhibit limited potency. In various literature reports, ribonuclease- targeting chimeras (RIBOTACs) exemplify this problem, achieving only ~75% maximum degradation of distinct RNA targets in cells. For example, our preliminary work optimized a synthetic RNA ligand, C34, which binds robustly to an RNA G bulge in the 5’ untranslated region of SARS-CoV-2’s RNA genome with a low nanomolar dissociation constant. However, the minimum inhibitory concentration (MIC) of the C34-based RIBOTAC remained moderately high at 20 μM in SARS-CoV-2-infected cells, indicating insufficient cellular potency. RIBOTAC is a drug-induced TRD modality utilizing an endogenous ribonuclease, RNase L. Interestingly, this RIBOTAC potency cap in cells was not observed in cell-free assays using purified recombinant RNase L, indicating the possible presence of cellular factors that inhibit the RNase L degradation complex. To address this potency limitation, the proposed project aims to discover novel cellular targets to significantly enhance RNase L activity and brand-new TRD mechanisms for future drug development through two specific aims. Aim 1 focuses on identifying cellular determinants that inhibit RNase L-dependent RIBOTAC activity using a genome-wide CRISPR knockout screen. By targeting these inhibitory genes, we aim to significantly boost the efficacy of existing RIBOTACs. Aim 2 focuses on discovering novel cellular targets for TRD by performing genome-wide screenings in three screening platforms. We will utilize a plasmid library comprising ~14,000 open reading frames from the human genome to identify candidate genes that can effectively induce TRD through drug-induced proximity. Both aims will leverage a SARS-CoV-2 cellular model and our optimized RNA ligand C34 to validate these new mechanisms in antiviral research. Ultimately, this project seeks to expand our chemical genetics toolbox by unveiling new mechanisms and targets for RNA degradation. These advancements will be pivotal in developing new chimeric molecules designed to combat a variety of infectious diseases, significantly enhancing our capacity to address global health challenges. 1
Grant Summary
Identification of Novel Targets for Enhancing Targeted RNA Degradation in Antiviral Discovery is a NIAID - National Institute of Allergy and Infectious Diseases grant providing up to $451K for university, nonprofit, healthcare org. Applications are due 2028-01-31 (open). Check eligibility and apply with FindGrants.
Focus Areas
Eligibility
How to Apply
Up to $451K
2028-01-31
- 1Confirm your organization is eligible for Identification of Novel Targets for Enhancing Targeted RNA Degradation in Antiviral Discovery from NIAID - National Institute of Allergy and Infectious Diseases, checking organization type, location, and any population or project requirements.
- 2Gather the required documents and information, including your organization details, project plan, and budget figures.
- 3Draft your application narrative and budget addressing the funder's priorities and review criteria. FindGrants can draft each section for you to review and edit.
- 4Review every section against the requirements checklist, then export a submission-ready application pack and submit it to NIAID - National Institute of Allergy and Infectious Diseases before the deadline.
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Identification of Novel Targets for Enhancing Targeted RNA Degradation in Antiviral Discovery: Frequently Asked Questions
Who is eligible for the Identification of Novel Targets for Enhancing Targeted RNA Degradation in Antiviral Discovery?
Identification of Novel Targets for Enhancing Targeted RNA Degradation in Antiviral Discovery is offered by NIAID - National Institute of Allergy and Infectious Diseases and is generally open to university, nonprofit, healthcare org. It is open to organizations nationwide unless the funder specifies otherwise. Review the specific eligibility terms before applying, since funders set their own requirements around organization type, location, and the population or project being served.
How much funding does the Identification of Novel Targets for Enhancing Targeted RNA Degradation in Antiviral Discovery provide?
Identification of Novel Targets for Enhancing Targeted RNA Degradation in Antiviral Discovery provides up to $451K per award from NIAID - National Institute of Allergy and Infectious Diseases. Actual award sizes depend on the scope of your project, available program funds, and the number of applicants, so build a budget that reflects realistic, allowable costs rather than the maximum figure.
When is the Identification of Novel Targets for Enhancing Targeted RNA Degradation in Antiviral Discovery deadline?
Applications for Identification of Novel Targets for Enhancing Targeted RNA Degradation in Antiviral Discovery are due 2028-01-31 (open). Because deadlines can change, verify the date with the funder, NIAID - National Institute of Allergy and Infectious Diseases, and give yourself enough time to prepare a complete, competitive application before the close date.
How do you apply for the Identification of Novel Targets for Enhancing Targeted RNA Degradation in Antiviral Discovery?
To apply for Identification of Novel Targets for Enhancing Targeted RNA Degradation in Antiviral Discovery, confirm your eligibility, gather the required documents, and prepare a narrative and budget that address the funder's priorities. FindGrants guides you step by step and can draft each section, then exports a submission-ready application pack for this grant from NIAID - National Institute of Allergy and Infectious Diseases.