# CHEMOPROTEOMIC METHODS FOR SERINE HYDROLASE INHIBITOR DEVELOPMENT

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2021 · $486,911

## Abstract

Enzymes perform many of the most vital functions in our cells and tissues and are the targets of numerous
transformative medicines. Considering the importance of enzymes in health and disease, it is both provocative
and humbling to realize that the human proteome contains a huge number of uncharacterized enzymes.
Assigning functions to these enzymes represents a grand challenge for researchers in the post-genomic era.
To achieve this goal, selective pharmacological tools to perturb enzymes in living systems are needed. A
pressing question, however, arises: how can one rapidly and systematically discover inhibitors for poorly
characterized enzymes? Over the past decade, our lab has pioneered the development and application of an
innovative chemical proteomic solution to this problem termed activity-based protein profiling (ABPP). The
objective of this application is to use ABPP to discover potent, selective, and in vivo-active inhibitors for serine
hydrolases (SHs), which are a large and diverse enzyme class that represents ~1% of all human proteins. SHs
play critical roles in human physiology and disease and are targeted by several approved drugs. Despite their
biological and biomedical importance, most SHs, including many with genetic links to human disease, lack
inhibitors and consequently remain poorly understood with regards to their physiologic substrates and
functions. In this this competitive renewal project, we will focus on inhibiting and functionally characterizing
SHs with established or emergent roles in neurobiological processes. During the previous grant period, we
created an efficient ABPP platform for SH inhibitor discovery and optimization that has already yielded
selective and in vivo-active inhibitors for several SHs, as well as lead inhibitors for many additional enzymes. In
most cases, these compounds represent the first pharmacological probes for studying their SH targets in living
systems and are in widespread use by the biology research community. In this application, we propose to use
a multidisciplinary research program that integrates ABPP with chemical synthesis, lipidomics, mouse
genetics, and cell and animal pharmacology to selectively inhibit and functionally characterize: 1) SHs that
regulate the biosynthesis of the endocannabinoid class of lipid transmitters in the nervous system (Specific Aim
1), and 2) SHs and SH pathways with genetic links to human neurological disorders (Specific Aim 2). We have
enlisted a strong set of biology collaborators who will apply our optimized inhibitors to mouse models of
nervous system function and disease. The inhibitors generated and knowledge gained herein should greatly
advance our understanding of the functions of SHs and SH pathways, enabling the identification of drug
targets to treat human neurological diseases.

## Key facts

- **NIH application ID:** 10133574
- **Project number:** 5R01DA033760-10
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** BENJAMIN F CRAVATT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $486,911
- **Award type:** 5
- **Project period:** 2012-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133574

## Citation

> US National Institutes of Health, RePORTER application 10133574, CHEMOPROTEOMIC METHODS FOR SERINE HYDROLASE INHIBITOR DEVELOPMENT (5R01DA033760-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10133574. Licensed CC0.

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