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From Fleeting States to Therapeutics: New Perspectives in Protein-RNA Binding Dynamics and their Role in Drug Discovery

Award Number: R21AI203185
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: 08/14/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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From Fleeting States to Therapeutics: New Perspectives in Protein-RNA Binding Dynamics and their Role in Drug Discovery - PROJECT SUMMARY The conventional approach to structural-knowledge driven drug discovery for protein targets often couples high-res- olution structural data (such as crystallography or electron microscopy) to identify potential binding sites with high- throughput computational docking simulations to optimize molecular design. While this approach, developed over decades, has been extremely productive for protein targets, it has limited applicability to unconventional targets like RNA and disordered proteins that are highly dynamic, sample rare and transient states that may contribute to bind- ing, and lack identiﬁable structure features that serve as high-aƯinity binding regions. These targets therefore lay outside the current druggable landscape. Progress extending this landscape requires the development of a compre- hensive understanding of the biophysics of currently undruggable biomolecules and new methodologies for identi- fying and characterizing unconventional targets. This proposal seeks to apply novel single-molecule spectroscopic methods, non-perturbative labeling, and computational modeling to help establish RNA stem loops, small RNA hair- pins that are critical regulatory molecules, as a viable target for peptide therapeutics. Using the trans-activation re- gion (TAR) RNA stem loop of the HIV1 virus as a model system, we seek to (Speciﬁc Aim 1) characterize the equilib- rium ensemble of the TAR molecule, (Speciﬁc Aim 2) resolve the binding mechanism between TAR and the native HIV1 polymerase as well as synthetic peptide mimics, and (Speciﬁc Aim 3) quantify state and nucleotide-resolved binding free energies to overcome the ensemble averaging limitation of conventional measurements of binding af- ﬁnities. Success of these aims is predicated on the unique information content of single-molecule spectroscopic data processed with multidimensional correlation function analyses, which has been shown to drastically expand the dynamic range of the spectroscopy (10-6-101s) and to be sensitive to ultra-rare conformations (<0.01% of an en- semble). Combining this new methodology with non-perturbative labeling provides a route to address the Speciﬁc Aims outlined above. Success in this project will provide a quantitative (thermodynamics and kinetics) mapping of protein-RNA interactions that can serve as the foundation for structure-knowledge based drug discovery. Further- more, comparing the binding mechanisms of HIV1 native polymerase protein with known cyclical peptides that are believed to mimic the binding will provide a productive road map for the further development and reﬁnement of pep- tide therapeutics. In addition to what is learned about the speciﬁc system of study, the technical methodologies and scientiﬁc approach developed over the course of this project will be completely generalizable to any RNA stem loop system. We anticipate that the experimental technique will be extended to studying the binding of RNA to any pro- tein, peptide, or small molecule binding partner.


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 = $222,516 )
2026	2026	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Allergy and Infectious Diseases Research	000	1	8/14/2026	NEW	$222,516
														Subtotal = $222,516

Grand Total All Awards = $222,516

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From Fleeting States to Therapeutics: New Perspectives in Protein-RNA Binding Dynamics and their Role in Drug Discovery

Award Number: R21AI203185

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: 08/14/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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