# Synthesis and evaluation of peptidomimetics to probe the active site of the botulinum neurotoxin to discover therapeutic leads for the treatment of botulism

> **NIH NIH R16** · CALIFORNIA STATE UNIVERSITY FULLERTON · 2024 · $131,248

## Abstract

Project Summary/Abstract
 The botulinum neurotoxin (BoNT) is the most lethal toxin known to man, with a lethal dose of only 1
ng/kg of body weight. The neurotoxin acts on neurons causing irreversible termination of
neurotransmission resulting in flaccid muscle paralysis diagnosed as botulism. Botulism is a serious illness
that can lead to respiratory failure and death. The intentional use of the extremely deadly neurotoxin as a
biological weapon is a major concern. Coupled with limited treatment options, there is an urgent need for
therapeutics to treat BoNT intoxication. The goal of this project is to create new molecules that are
therapeutically sound leads for the treatment of botulism.
 Previously, we have discovered the dipeptide scaffold as a potent source of BoNT inhibitors via
enzymatic inhibition assay and X-ray crystallography. This is the first reported example of dipeptides as a
BoNT inhibitor. We propose that the dipeptide is an excellent scaffold for BoNT inhibitor design and will
create dipeptides with potent inhibitor activity and optimize the pharmacokinetic properties. The aims of
this proposed research are 1) Synthesize dipeptide libraries to study BoNT inhibition; 2) Evaluate the
dipeptides as BoNT inhibitors through enzyme inhibition assays; 3) Examine pharmacokinetic properties
of the dipeptides by performing cell permeability and metabolic stability studies. Based on the results from
aims 2 and 3, structural improvements will be made to the peptides to allow for the synthesis of 2nd and
3rd-generation dipeptides that are enriched with potent inhibitors, which have excellent cell permeability
and metabolic stability. Overall, the proposed research will deliver true therapeutic lead compounds with
potent inhibitor activity with promising pharmacokinetic profiles. This work will provide a novel scaffold that
will be a sound therapeutic lead for the treatment of botulism. Undergraduate student researchers will
perform all aspects of the proposed research. Research laboratory experiences will be transformative for
undergraduate students and help improve their career trajectory. The research described will provide
undergraduate students with laboratory training that will be valuable for their future careers in biomedical
research.

## Key facts

- **NIH application ID:** 10848110
- **Project number:** 1R16AI175003-01A1
- **Recipient organization:** CALIFORNIA STATE UNIVERSITY FULLERTON
- **Principal Investigator:** Nicholas Thomas Salzameda
- **Activity code:** R16 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $131,248
- **Award type:** 1
- **Project period:** 2024-04-11 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848110

## Citation

> US National Institutes of Health, RePORTER application 10848110, Synthesis and evaluation of peptidomimetics to probe the active site of the botulinum neurotoxin to discover therapeutic leads for the treatment of botulism (1R16AI175003-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10848110. Licensed CC0.

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