# Discovery and use of chemical probes through SuFEx chemistry, computational design and predictive modeling

> **NIH NIH U54** · SEATTLE CHILDREN'S HOSPITAL · 2021 · $283,340

## Abstract

ABSTRACT
Chemical biology is playing an increasing role in helping to discover and elucidate the structural and
mechanistic aspects of complex biomolecular systems. Project 6 will develop chemical probes for use in
functional analysis and fluorescent labeling of critical structures and assemblies in the HIV life cycle, as well as
design new modes of inhibition in drug resistant targets. The project will take a multipronged approach, built
around the highly innovative Sulfur (VI) Fluorine Exchange (SuFEx) chemistry for discovering and designing
reactive yet bioorthogonal specific molecules to selectively target macromolecules involved in the viral life
cycle. SuFEx chemistry has shown great success in discovery of new binding modes to a wide variety of
targets. Computational methods will complement this chemistry: ultrahigh-throughput virtual screening with
reactive docking will add rational design to the method, and mesoscale modeling will integrate diverse data
from the HIV structural community into models of viral and host protein assemblies. The project involves close
collaborations with other HIVE investigators who will provide experimental assays and verification of the
methods, hypotheses, and reagents that are developed. The combination of chemistry and computation will
complement and extend the structural and functional data gathered by experiments proposed in other projects,
serving the following specific aims:
1) Design and create diversity oriented rational SuFEx moiety-containing library of irreversible binding probes
for activity/function modulation of HIV targets;
2) Virtual screening, reactive docking and free energy perturbation calculations for modulation of protein-
protein and protein-nucleic acid interactions of viral and host macromolecules;
3) Modeling, structure- and evolutionary sequence-based rational design of new allosteric HIV Integrase
inhibitors;
4) Development of mesoscale integrative HIV modeling for inhibitor and drug target discovery.
The project will design novel computational protocols to generate and test new hypotheses by integrating the
large amount of structural and biochemical data generated in other HIVE Projects. These models will provide
rational support driving the design of new molecular probes, and lead to new drug design methodologies and
therapeutic advances to treat HIV infected patients who have developed drug resistance to standard therapies.
The SuFEx chemistry effort will be led by Sharpless, and the computational work will involve Olson, Goodsell
and Levy, with outside collaborators Viola, and Wade. Experimental assays and hypothesis validation will
involve the laboratories of HIVE investigators Torbett, Kvaratskhelia, Sarafianos, Arnold, Musier-Forsyth,
Lyumkis, Millar, Williamson, Marcotrigiano and Griffin.

## Key facts

- **NIH application ID:** 10242910
- **Project number:** 5U54AI150472-11
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** ARTHUR J. OLSON
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $283,340
- **Award type:** 5
- **Project period:** 2012-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242910

## Citation

> US National Institutes of Health, RePORTER application 10242910, Discovery and use of chemical probes through SuFEx chemistry, computational design and predictive modeling (5U54AI150472-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10242910. Licensed CC0.

---

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