# Experimental characterization and computational modeling of intrinsic bioreactivity of SuFEx/covalent nucleophile warheads

> **NIH NIH U54** · SEATTLE CHILDREN'S HOSPITAL · 2024 · $253,415

## Abstract

Project Abstract
Targeted covalent inhibitors (TCI) represent a powerful but underexploited chemistry for targeting challenging
and uncharacterized protein structures, especially therapeutically relevant targets. Among the many
electrophilic warheads capable of modifying proteins, sulfonyl-fluoride exchange chemistry (SuFEx) are
among the most chemically versatile. SuFEx combines high modification yields with broad cellular proteome
coverage due to the targeting of Lys, Tyr, Ser, and His residues that are abundant among viral, bacterial, and
eukaryotic proteomes (i.e., compared with the relatively low abundance of cysteines targeted by most other
warheads). Given the broad coverage by SuFEx warheads, they would be an invaluable tool to target HIV-1
protein targets as well as their interactions with cellular proteins, where reactive cysteines may be absent.
Despite the great potential of SuFEx warheads as chemical probes, and efforts from both academia and
industry to develop the methodology, they are heavily underexploited given that the breadth of their intrinsic
chemical reactivity has not been fully characterized and cataloged. Thus, there is a need to determine SuFEx
chemistry intrinsic reactivity to allow the development of predictive models. This information can be used to
design SuFEx warheads to provide the appropriate activity for covalent modification. This proposal seeks to
address this need by experimentally determining the intrinsic reactivity of a large number of SuFEx probes,
spanning the largest commercially available chemical space, and to develop quantum mechanics and
machine learning models to predict these reactivities in a drug/probe design setting. A prospective virtual
screen incorporating this information will be performed against HIV CA, leading to new chemical matter in a
novel ligand class against this protein.

## Key facts

- **NIH application ID:** 10841223
- **Project number:** 3U54AI170855-03S1
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Stefan G Sarafianos
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $253,415
- **Award type:** 3
- **Project period:** 2022-06-22 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841223

## Citation

> US National Institutes of Health, RePORTER application 10841223, Experimental characterization and computational modeling of intrinsic bioreactivity of SuFEx/covalent nucleophile warheads (3U54AI170855-03S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10841223. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*