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Advanced Nucleation Technologies for Membrane Protein Crystallization to Accelerate Structure-Based Drug Design for Substance Use Disorders

Award Number: R44DA047146
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Advanced Nucleation Technologies for Membrane Protein Crystallization to Accelerate Structure-Based Drug Design for Substance Use Disorders - PROJECT SUMMARY DeNovX creates innovative platform products that improve the crystallization of proteins and pharmaceuticals. Of the ≈ 4700 human membrane proteins potentially involved in drug responses, ≈ 94% have yet to be structurally characterized owing to difficulties in crystallization. The goal of Phase II is to adapt DeNovX’s surface science agnostic approach to improving crystallization for use with membrane proteins to advance the structure-based understanding of substance use disorders (SUDs) to benefit Public Health. DeNovX improves crystallization using tunable substrates based on chemical interactions from bifunctional self-assembled monolayers (SAMs); surface energy modifications from engineered nucleation features (ENFs); and a hybrid strategy using chemically and energy modified ENFs (CENFs). A high confidence POC was achieved using the membrane proteins quinol:fumarate reductase (QFR) and succinate:quinone oxidoreductase (SQR). Diffraction quality QFR crystals were formed on a bifunctional SAM while no crystals formed on controls, and select ENFs produced up to a 19-fold increase in QFR crystals vs. controls. The hypothesis is that bifunctional SAMs, ENFs, or hybrid CENFs interacting with a membrane protein or its detergent envelope can facilitate preorganization and crystal nucleation from supersaturated solutions. Specific Aim 1 - Conduct controlled, replicate (n ≥ 6) studies of membrane protein crystallization outcomes using β-prototype bifunctional SAMs, ENFs, and CENFs to identify those characteristics most favorably impacting crystal nucleation of the QFR and SQR benchmark membrane proteins provided by Co-I Iverson under a subaward to Vanderbilt. These rigorous and quantitative crystallization studies will be complemented with synchrotron X-ray diffraction to ensure resolution that supports binding and conformational analyses through a subaward to Co-I Cohen at Stanford’s Synchrotron Radiation Lightsource (SSRL). Specific Aim 2 - Incorporate surface characteristics most favorably impacting membrane protein crystallization into bifunctional SAM, ENF, and CENFs on ≥ 12 -prototype 24/96/384 well HTS crystallization plates. Optimize for crystallization in detergent containing systems and advance development of the top six nucleation surfaces showing reproducible (n ≥ 6) crystallization improvements of ≥ 15% increase in hits, ≥ 20% reduction in onset times, or ≥ 25% increase in the quantity of crystals generated vs. controls. Specific Aim 3 - Incorporating SUD relevant target guidance from NIH and domain experts with a tractability assessment by the Co-Is, expand crystallization screening with optimized nucleation surfaces to ≥ 8 membrane proteins of varying class that would most benefit from near atomic resolution structural data. Generate crystals for ≥ 2 targets for study at SSRL. Specific Aim 4 - Demonstrate the tangible benefits and deploy the surface science product suite for membrane protein crystallization screening with pharmaceutical company, NIH, and academic researchers to facilitate therapeutic target identification for SUDs. DeNovX will sell its patented high throughput crystallization plates in a $450M-650M market.


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: 2023 ( Subtotal = $711,255 )
2023	2023	DENOVX, LLC	3440 S DEARBORN ST # 204-S	CHICAGO	IL	60616	COOK	USA	Drug Use and Addiction Research Programs	000	3	8/9/2023	NON-COMPETING CONTINUATION	$711,255
														Subtotal = $711,255

Issue Date FY: 2022 ( Subtotal = $1,775,613 )
2022	2022	DENOVX, LLC	3440 S DEARBORN ST # 204-S	CHICAGO	IL	60616	COOK	USA	Drug Use and Addiction Research Programs	000	2	9/20/2022	COMPETING CONTINUATION	$1,775,613
														Subtotal = $1,775,613

Grand Total All Awards = $2,486,868

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Advanced Nucleation Technologies for Membrane Protein Crystallization to Accelerate Structure-Based Drug Design for Substance Use Disorders

Award Number: R44DA047146

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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