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Cycling Molecular Assemblies (CyMA) for Cell-Selective Disruption of Golgi-Mediated Trafficking via Enzyme-Driven Supramolecular Localization

Award Number: R01GM167078
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/04/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2030

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Cycling Molecular Assemblies (CyMA) for Cell-Selective Disruption of Golgi-Mediated Trafficking via Enzyme-Driven Supramolecular Localization - Abstract Cellular transport is essential for determining cell fate, with Golgi-mediated vesicular trafficking playing a central role in coordinating the sorting, modification, and delivery of proteins and lipids throughout the cell. This trafficking system not only supports fundamental cellular functions but also integrates key signaling pathways that dictate development, immune responses, and disease progression. Despite its critical importance, Golgi- mediated trafficking remains a difficult therapeutic target due to pathway redundancy and limited cell specificity. We have unexpectedly discovered cycling molecular assemblies (CyMA), first-in-class supramolecular structures that are non-diffusive and enable cell-selective, pleiotropic targeting of Golgi-mediated vesicular trafficking. Unlike traditional drug design, which emphasizes specific binding, CyMA operate through kinetic control, engaging in futile enzymatic cycles mediated by acylases and deacylases. These reactions drive reversible intracellular lipidation and promote CyMA accumulation at the Golgi, thus disrupting vesicular trafficking. CyMA offer several compelling advantages: (i) They do not rely on binding to a single protein, enabling broad modulation of multiple pathways. (ii) They enable organelle-level control over diverse protein functions, potentially enhancing therapeutic efficacy. (iii) They can disrupt Golgi-mediated vesicular trafficking, producing distinct biological outcomes such as impaired cell proliferation and selective cell death. (iv) Because CyMA form non-diffusive assemblies localized specifically at the Golgi, they overcome key limitations of conventional small molecules, such as passive diffusion and lack of cell selectivity. This property promises to achieve cell-, tissue-, and cancer-specific targeting. The goal of this proposal is to develop CyMA as a supramolecular technology for cell-selective disruption of vesicular trafficking, guided by two specific aims: Aim 1 – Establish molecular design principles for CyMA to enable cell-selective disruption of Golgi-mediated trafficking; Aim 2 – Define the mechanism of action of CyMA in disrupting protein trafficking and inducing cell death. By accomplishing these aims, we anticipate that using CyMA to target Golgi-mediated vesicular trafficking will unlock new therapeutic frontiers in previously underexplored spaces, such as the Golgi. This work aligns with the goals of the Focused Technology Research and Development initiative (PAR-25-203), which supports the advancement of technologies with demonstrated proof-of-concept for broad implementation. Ultimately, this research will open new directions in cell biology, disease mechanisms, and therapeutic innovation.


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 = $525,039 )
2026	2026	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Biomedical Research and Research Training	000	1	9/4/2026	NEW	$525,039
														Subtotal = $525,039

Grand Total All Awards = $525,039

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Cycling Molecular Assemblies (CyMA) for Cell-Selective Disruption of Golgi-Mediated Trafficking via Enzyme-Driven Supramolecular Localization

Award Number: R01GM167078

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/04/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2030

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