# Selective inhibition of nitric oxide synthase for multiple indications

> **NIH NIH R35** · NORTHWESTERN UNIVERSITY · 2023 · $429,644

## Abstract

Project Summary
 This proposal is a continuation of R01 GM049725, “Selective Inhibition of Nitric Oxide
Synthase for Multiple Indications”. Nitric oxide synthase (NOS) is a remarkable target, as we have
found that neuronal nitric oxide synthase (nNOS) inhibitors are applicable to the potential treatment of
neurodegenerative diseases (e.g., Parkinson's, Alzheimer's, cerebral palsy), bacterial infection, and
melanoma. Inhibitors of nNOS block the excess NO that can cause degeneration of neurons. They
also inhibit NO produced in melanocytes that leads to melanoma. Inhibitors of bacterial NOS (very
similar to nNOS) can be used to protect antibiotics from bacterial degradation (i.e., resistance) and
can be synergistic for bacterial growth inhibition by oxidant stress molecules, such as hydrogen
peroxide. We have made outstanding progress on all three indications; two of which could not have
progressed without the crystallography expertise of Thomas Poulos. In the last four years we have
been able to shorten the syntheses of our inhibitors, make inhibitors that are membrane penetrable,
are stabilized from metabolism, and are blood-brain barrier (BBB) penetrable with good oral
bioavailability while maintaining excellent potency and nNOS selectivity. However, we have not yet
gotten compounds that possess all of the desired properties. Consequently, this grant will allow us to
identify compounds that have all of the desired pharmacodynamics and pharmacokinetic properties.
 We plan to optimize our nNOS-selective compounds for pharmacodynamics and
pharmacokinetics and test in mouse models of Parkinson's and Alzheimer's diseases and in a rabbit
model for cerebral palsy.
 We have identified several nNOS-selective compounds that inhibit the growth of bacteria,
including MRSA, especially in combination with an antibiotic or hydrogen peroxide. We plan to make
bacterial NOS (bNOS)-selective compounds to avoid potential side effects from inhibition of
mammalian NOS. Also, there may be additional targets, other than bNOS with which our compounds
interact; therefore, we will carry out protein pulldown experiments with a photoaffinity-labeled bNOS
inhibitor and identify proteins to which it attaches with proteomics. This should clarify a more
complete mechanism of action of bNOS inhibitors.
 Our best nNOS-selective inhibitors will also be tested by Dr. Sun Yang as inhibitors of a variety
of melanoma cell lines and in a xenograft melanoma model for inhibition of melanoma growth and
metastasis. Dr. Yang has identified a peptide carrier to target molecules to melanoma; we will
conjugate active compounds to this peptide for drug delivery. We also will make a photoaffinity probe
of an active inhibitor to identify targets.

## Key facts

- **NIH application ID:** 10611534
- **Project number:** 5R35GM131788-05
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** RICHARD B SILVERMAN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $429,644
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10611534

## Citation

> US National Institutes of Health, RePORTER application 10611534, Selective inhibition of nitric oxide synthase for multiple indications (5R35GM131788-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10611534. Licensed CC0.

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