# Project 2: Advancing glyoxylate as a chemical countermeasure

> **NIH NIH U54** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $370,586

## Abstract

Although several compounds with cyanide antidote activity exist, all function via stoichiometric reaction
with free cyanide to form a less-toxic cyanide complex. As such, these cyanide scavengers only work at
stoichiometric doses and only prior to cyanide interacting with its target proteins. A cyanide countermeasure
that did not rely solely on scavenging of free cyanide would be a highly-valuable addition to the
countermeasure arsenal because it could potentially 1) be effective at sub-stoichiometric doses, 2) be used in
combination with existing scavenging agents, and 3) provide benefit even after cyanide had bound to its
cellular targets. Recent discovery efforts within our consortium have identified glyoxylate as a potent and highly
effective cyanide countermeasure. Treatment with glyoxylate rescues zebrafish, mice, and rabbits exposed to
cyanide. Remarkably, glyoxylate does not appear to be functioning only as a cyanide scavenger. Rather, it
appears to produce a rapid and dramatic metabolic transformation that normalizes several key metabolic
derangements induced by cyanide, including perturbations in oxygen consumption, metabolite flux, and redox
balance. Thus, glyoxylate appears to function through a mechanism that is very different from existing
scavenger-based cyanide countermeasures. As such, it may complement existing countermeasures and
provide a completely novel means of reversing cyanide's effects.
 In this project we will focus on delivering one or more glyoxylate-based countermeasure products.
Efforts will include optimization of glyoxylate derivatives for use as cyanide antidotes through standard
formulation and optimization strategies. We will also explore LDH, the presumptive glyoxylate target, as a
potential source of second-generation cyanide antidotes. Finally, we will test the ability of glyoxylate to rescue
the effects of other metabolic poisons, sulfide and azide. Specific aims include:
Aim 1. To optimize glyoxylate as a countermeasure for clinical deployment. This aim focuses on
formulation of glyoxylate to produce a stable countermeasure product that can be delivered by autoinjector.
Aim 2. To develop alternative LDH substrates as second-generation, glyoxylate-like countermeasures.
This aim explores a series of alternative LDH substrates as potential cyanide countermeasures through studies
in zebrafish, mice, and rabbits.
Aim 3. To test glyoxylate as a countermeasure for other metabolic poisons. This aim tests the ability of
glyoxylate to reverse the toxic effects of other metabolic poisons including sulfide and azide.
 Successful completion of this project will deliver at least one fully validated, glyoxylate-based cyanide
countermeasure that meets the BARDA requirements for advanced development. It will also fill the pipeline
with second-generation countermeasures that exploit metabolic modulation to counteract cyanide toxicity.
.

## Key facts

- **NIH application ID:** 10241502
- **Project number:** 5U54NS112107-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** RANDALL T PETERSON
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $370,586
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241502

## Citation

> US National Institutes of Health, RePORTER application 10241502, Project 2: Advancing glyoxylate as a chemical countermeasure (5U54NS112107-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10241502. Licensed CC0.

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