# Cell permeant peptidomimetics to prevent delayed vasospasm and neurological deficits after subarachnoid hemorrhage

> **NIH NIH R41** · VASAMETRIX LLC · 2022 · $261,863

## Abstract

PROJECT SUMMARY
 Subarachnoid hemorrhage (SAH) due to rupture of an intracranial aneurysm leads to delayed
vasospasm resulting in neuroischemia (stroke). The overall morbidity (profound neurologic deficit in
10-20% of survivors) and mortality (50%) are high, and the disease affects a relatively young adult
population. Therapeutic options to prevent delayed vasospasm and neuroischemia after SAH are
currently limited to hemodynamic optimization and nimodipine, which have marginal clinical efficacy.
Thus, treatment of delayed vasospasm after SAH represents an unmet clinical need in an orphan
population with severe clinical consequences.
 Attempts to treat SAH-induced vasospasm with existing vasodilators often fail because of systemic
hypotension (leading to decreased cerebral perfusion) and a cerebral vasculature that is refractory to
activation of nitric oxide (NO)-dependent signaling pathways.5 NO signaling modulates vascular
smooth muscle (VSM) relaxation and regulation of cerebral blood flow. The impaired response of
cerebral vessels to vasodilators, i.e. impaired vasorelaxation after SAH, is likely due to down regulation
of the signaling elements in the NO pathway after SAH. The hypothesis of this investigation is that
treatment with a rationally designed, cell permeant phosphopeptide mimetic of a downstream effector
protein of the NO pathway will bypass downregulated signaling elements, restore vasorelaxation, and
prevent delayed vasospasm after SAH. This approach is more targeted and stoichiometric than
approaches that activate or inhibit receptors or enzymes. In addition, this approach is particularly
useful in SAH where preventing systemic hypotension and optimizing cerebral vasodilation is
paramount.
 A family of cell permeant phosphopeptide analogues of a substrate of cGMP-dependent Protein
Kinase (PKG), and an actin-associated protein that modulates VSM relaxation, were rationally designed
and synthesized. Three candidate peptides were demonstrated to directly relax intact VSM in ex vivo
bioactivity assays. The peptide with the shortest sequence (denoted as VP3) and strongest bioactivity
was chosen as the optimal peptide for use to determine in vivo efficacy.

## Key facts

- **NIH application ID:** 10384341
- **Project number:** 1R41NS122656-01A1
- **Recipient organization:** VASAMETRIX LLC
- **Principal Investigator:** Colleen M Brophy
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $261,863
- **Award type:** 1
- **Project period:** 2022-02-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10384341

## Citation

> US National Institutes of Health, RePORTER application 10384341, Cell permeant peptidomimetics to prevent delayed vasospasm and neurological deficits after subarachnoid hemorrhage (1R41NS122656-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10384341. Licensed CC0.

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