# Chemical biology approaches to probe signaling by protein lipidation

> **NIH NIH R35** · UNIVERSITY OF CHICAGO · 2022 · $429,750

## Abstract

Project Summary
Protein lipidation is a dynamic post-translational modification (PTM) that affects subcellular
trafficking, co-factor binding affinity, and membrane localization of proteins, which in turn
influence downstream signaling cascades. In particular, cyclic S-acylation and -deacylation of
proteins at specific cysteine residues is emerging as a key link between circulating lipid levels and
the regulation of essential biological processes, including those involved in cellular growth,
metabolism, and neurological health. In-depth study of this PTM, however, has proven technically
difficult, in large part due to the paucity of selective, effective chemical inhibitors for the enzymes
that catalyze its installation and removal. The proposed research program is designed to
generate novel chemical technologies, namely small molecule probes and inhibitors, in the
service of illuminating the involvement of regulated protein S-acylation in both normal and
pathophysiological contexts. These goals will be realized through two complementary chemical
and cellular biology research areas. One area will involve measuring, manipulating, and
determining the targets of the “writers” of S-acylation, DHHCs. To do so, pan-active DHHC
inhibitors will be identified using newly developed and optimized screening and selectivity profiling
assays in combination with rationally and computationally designed molecules, as well as a
library of putative inhibitors. Validated inhibitors and proteomics-based methods will then be used
to identify the specific protein targets of DHHCs in live cells to more precisely describe their
involvement in various disease states. The second research area will utilize our recently validated
chemical tools to study the biological function of the “erasers” of S-acylation, APTs, with particular
emphasis on the involvement of these enzymes in cellular redox homeostasis and metabolic
disease. The expected outcome of this multidisciplinary research program is two-fold: generating
a collection of chemical tools and assays for the study of this important PTM, and describing its
biological function and influence in normal and disease states.

## Key facts

- **NIH application ID:** 10403936
- **Project number:** 5R35GM119840-07
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Bryan Dickinson
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $429,750
- **Award type:** 5
- **Project period:** 2016-07-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10403936

## Citation

> US National Institutes of Health, RePORTER application 10403936, Chemical biology approaches to probe signaling by protein lipidation (5R35GM119840-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10403936. Licensed CC0.

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