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Development of Selective Antiviral RNA-Degrading Chimeras Mimicking Ribonuclease Activity

Award Number: R21AI199121
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/09/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Development of Selective Antiviral RNA-Degrading Chimeras Mimicking Ribonuclease Activity - PROJECT SUMMARY Endogenous ribonucleases (RNases) are an important component of the host immune response to viral infections. Mimicking the RNase function, RNA-degrading chimeras (RDC) are a class of molecules that selectively bind RNA and recruit RNases, typically RNase L, to cleave the viral RNA. However, RNase L- dependent RDCs typically achieve only ~75% RNA knockdown, insufficient for complete viral clearance. To overcome this limitation, we propose to develop a novel class of direct-acting antivirals: RDCs that cleave RNA directly through general acid–general base catalysis, more faithfully mimicking the mechanism of natural ribonucleases. Additionally, we will improve the selectivity of RNA-binding scaffolds by targeting a conserved viral RNA structure and developing a high-throughput synthesis and screening pipeline. Importantly, we will implement a second-generation chemical-guided SHAPE sequencing (cgSHAPE-seq) technology for activity- based RNA profiling. This platform will enable competitive, transcriptome-wide evaluation of ligand binding specificity in live cells. We will demonstrate the effectiveness of this new approach to antiviral design in the context of Zika virus (ZIKV), a mosquito-borne flavivirus associated with severe neurological disorders, including Guillain-Barré syndrome and microcephaly. We hypothesize that our optimized RDCs will significantly reduce ZIKV RNA levels both in vitro and in ZIKV-infected human neural progenitor cells. This project represents the first application of RDCs to directly degrade ZIKV RNA and introduces a generalizable strategy for RNA-targeting antiviral development. By establishing robust methods for RNA binding optimization and transcriptome-wide selectivity profiling, this work has the potential to revolutionize antiviral drug discovery and provide a scalable approach to combat emerging RNA viral threats. 1


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $442,296 )
2026	2026	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	1	6/11/2026	NEW	$442,296
														Subtotal = $442,296

Grand Total All Awards = $442,296

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Development of Selective Antiviral RNA-Degrading Chimeras Mimicking Ribonuclease Activity

Award Number: R21AI199121

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/09/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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