# Discovering novel metabolic targets to mitigate cyanide toxicity

> **NIH NIH U54** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $351,151

## Abstract

Summary
Cyanide is fundamentally a metabolic toxin. Although it has many known targets, many
of its pathological consequences can be ascribed to inhibition of mitochondrial
respiration through inactivation of Complex IV of the electron transport chain. Given this
prominent role of metabolism in the pathophysiology of cyanide poisoning, we expect
that modulators of metabolism might have potential as therapeutic countermeasures. In
fact, this Center has recently discovered that the metabolite glyoxylate profoundly
mitigates cyanide lethality in zebrafish, mice and rabbits. We propose to build upon this
foundation by defining the metabolic functions of this and other agents and testing the
hypothesis that redox imbalance underlies cyanide toxicity. We have further discovered
that activators and substrates of the TCA cycle also confer cyanide resistance and
propose to further develop such agents as therapeutics as well as complete our highly
focused screen of metabolites and metabolic modulators. We also propose a series of
mechanistic experiments to interrogate the extent to which Complex IV inhibition is the
mechanism of cyanide toxicity and the organs that mediate that toxicity. These studies
will synergize with experiments aimed at understanding the metabolic physiology of
cyanide toxicity and the response to various mitigating approaches. We hypothesize
that a deeper understanding of the metabolic basis of cyanide toxicity and mitigation will
inform a rational approach to countermeasures and their appropriate application.

## Key facts

- **NIH application ID:** 10241503
- **Project number:** 5U54NS112107-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Jared P Rutter
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $351,151
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241503

## Citation

> US National Institutes of Health, RePORTER application 10241503, Discovering novel metabolic targets to mitigate cyanide toxicity (5U54NS112107-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10241503. Licensed CC0.

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