# Novel Therapeutics for Heart Failure: Modified, Water-Soluble Caveolin-1 Scaffolding Domain Peptides with Improved Characteristics for Drug Development

> **NIH NIH R41** · FIBROTHERAPEUTICS, INC. · 2024 · $6,500

## Abstract

Abstract
Our long-term objective is to fill the unmet need for treatments for heart failure (HF). Caveolin-1 is a promising
therapeutic target in fibrotic diseases. The profibrotic effects of caveolin-1 deficiency in cells and in mouse
models is suppressed by a peptide equivalent to its active site (caveolin-1 scaffolding domain, CSD). We have
shown the beneficial effects of CSD in two independent models of PO-induced cardiac disease [transverse
aortic constriction (TAC) and angiotensin II (AngII) infusion] and also in aged mice. In all these models, CSD
almost completely suppressed pathological alterations in ventricular function, fibrosis, and microvascular
leakage. However, CSD lacks suitable pharmacologic properties for drug development. To address this issue,
we developed novel, modified versions of CSD. We first divided CSD into three subregions (amino acids 82-
89, 88-95, 94-101) and found they all suppressed fibrotic disease in vivo. To improve their pharmacology, we
modified CSD and each subregion to be water soluble and protected from proteolysis. This modification also
enhanced their uptake by cells and increased their ability to inhibit several purified kinases in vitro. So far, we
have only had the opportunity to test the modified, water-soluble version of 82-89 (W82-89) in an HF model.
W82-89 would be an excellent Lead Compound based on its effects on cardiac hypertrophy, fibrosis, and
microvascular leakage. However, because of the distinct pharmacological properties of our four modified
peptides, it is quite possible that another peptide is more effective than W82-89. Thus, to select a Lead
Compound, we will perform a side-by-side comparison of the four candidates. We will then determine the
Therapeutic Index (ratio between toxic and beneficial doses) of the Lead Compound. Specifically, we will: 1)
Select a Lead Compound using two model systems: AngII- and Isoproterenol-Induced HF. AngII and isoproter-
enol infusion are two frequently used, mechanistically distinct, model systems for inducing HF in mice. Studies
will be performed both in a prophylactic and in a therapeutic format (i.e. treatment begins only after disease is
established). We will consider these studies to be a success if a Lead Compound is selected that suppresses
the pathological effects of AngII and isoproterenol on ventricular function (Ejection Fraction [EF], fractional
shortening [FS], isovolumic relaxation time [IVRT]) and cardiac hypertrophy [heart weight/body weight ratio] by
>50% and the effects on fibrosis and microvascular leakage by >75%. 2) Determine the Therapeutic Index of
the Lead Compound. The dose-dependence of the Lead Compound’s beneficial effects will be determined
using doses above and below our current standard dose. Its toxicity will be evaluated in a Single-Treatment
Maximum Tolerated Dose Experiment using 1X, 5X, 25X, and 125X our current standard dose. We will
consider these studies to be a success if the Therapeutic Index is >50. In summa...

## Key facts

- **NIH application ID:** 10932654
- **Project number:** 3R41HL167327-01S1
- **Recipient organization:** FIBROTHERAPEUTICS, INC.
- **Principal Investigator:** STANLEY R HOFFMAN
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $6,500
- **Award type:** 3
- **Project period:** 2023-10-18 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932654

## Citation

> US National Institutes of Health, RePORTER application 10932654, Novel Therapeutics for Heart Failure: Modified, Water-Soluble Caveolin-1 Scaffolding Domain Peptides with Improved Characteristics for Drug Development (3R41HL167327-01S1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10932654. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*