# MAOI-inspired activity probes to translate epigenetics and genetics into drugs

> **NIH NIH DP1** · UNIVERSITY OF PENNSYLVANIA · 2020 · $486,000

## Abstract

Project Abstract
 Identification of genetic and epigenetic changes associated with disease states can
afford deep insight into the underlying molecular processes, but, particularly for diseases of the
central nervous system (CNS), translating this information to new drug therapies remains a
challenge. Here, we will exploit the chemistry of pharmacophores found in psychoactive drugs
to study the impact of genetic variants and epigenetic modifications in addiction. Hydrazine-
based drugs including monoamine oxidase inhibitors (MAOI) have a long history of success in
treating CNS disorders. The hydrazine group covalently inactivates several classes of enzymes
(e.g. oxidases, oxygenases, demethylases, hydroxylases) in the CNS that participate in
transcriptional regulation and chromatin remodeling, thereby contributing to a broad range of
biological functions and disease pathologies. I previously developed a novel chemical
proteomics discovery platform (which I dubbed `RP-ABPP) by exploiting the unique reactivity
(reverse polarity, RP) of this pharmacophore to create unbiased probes to target these enzyme
classes by activity-based protein profiling (ABPP). Given the established ability of hydrazine
drugs to reach the CNS and manipulate its biochemistry, this project will implement first-in-
class, nucleophilic brain-penetrating probes using our RP-ABPP platform to discover hydrazine-
sensitive enzymes disrupted in preclinical models of drug addiction. Specifically, these probes
will evaluate changes to the brain during the development of dependence using electronic
nicotine delivery systems (ENDS) with a newly established mouse model of inhalation exposure.
The goals are to i) identify novel druggable enzyme targets that are dysregulated in nicotine
dependence and ii) develop a suite of selective probes that can be used by neuroscientists as
pharmacological tools to study drug abuse and other psychiatric disorders. This platform is
expected to i) create new opportunities to map functional consequences of genetic mutations
and epigenetic modifications in drug dependence, ii) discover new druggable enzyme activities
that can be spatially mapped by imaging, and iii) ultimately create a unique opportunity for
therapeutic development around a relatively underexplored chemical space.

## Key facts

- **NIH application ID:** 10045180
- **Project number:** 1DP1DA051620-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Megan L Matthews
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $486,000
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10045180

## Citation

> US National Institutes of Health, RePORTER application 10045180, MAOI-inspired activity probes to translate epigenetics and genetics into drugs (1DP1DA051620-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10045180. Licensed CC0.

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