# Tools to Study Electrophilic Stress and Develop Covalent Drugs

> **NIH NIH R35** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $305,000

## Abstract

Abstract
Reactive electrophile species constantly modify biomolecules and impact human health in ways that are still
poorly understood. This research program establishes the methodological groundwork to rigorously test
hypotheses regarding reactive electrophilic species and to develop new covalent irreversible drugs. Bioactive
electrophiles such as α,β-unsaturated carbonyls are present in the environment and diet, but they are also
produced endogenously during metabolism and oxidative stress. They have been linked to the etiology of diverse
pathological states such as atherosclerosis, cancer, neurodegeneration, and inflammation. Understanding the
roles of reactive electrophilic species in homeostasis and disease will provide important guidance for disease
prevention and the development of new therapeutics. However, a lack of research tools has impeded such
endeavors and many studies in this field lack experimental rigor. The problem is that these reactive electrophilic
species irreversibly modify a large number of biomolecules with very little control by the scientist. The program
will close critical methodological gaps in the research on the effects of electrophiles in biology. Anticipated
deliverables are methods that enable the controlled generation of such electrophiles at specific times and
locations. Furthermore, methods to controllably reverse the formed covalent adducts of such electrophiles will
be developed. Additionally, screening technologies to develop molecules that target specific protein residues will
be established. The methods are innovative because they allow answering important biomedical questions that
are currently out of reach. The program’s preliminary studies have established a solid foundation to achieve
these goals. We have developed chemical reactions that allow generating α,β-unsaturated carbonyls on-demand
in living systems, and we have established DNA-encoded libraries for the discovery of bioactive species. With
these unique capabilities in hand, the research program is in the position to advance the understanding of
reactive electrophilic species in biology and their impact on disease. To demonstrate their utility, we will apply
them to study the involvement of 4-hydroxynonenal in atherosclerosis and study the dynamics of adaptive states
associated with resistance to KRASG12C inhibitors of pancreatic cancer. We will take steps to ensure that the
developed methods will be available to a broad range of scientists to maximize the impact of the program.

## Key facts

- **NIH application ID:** 10404013
- **Project number:** 5R35GM138335-03
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Raphael M. Franzini
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $305,000
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10404013

## Citation

> US National Institutes of Health, RePORTER application 10404013, Tools to Study Electrophilic Stress and Develop Covalent Drugs (5R35GM138335-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10404013. Licensed CC0.

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