# Novel  Peptide Therapeutics for Hypertension

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2021 · $614,866

## Abstract

PROJECT SUMMARY
The objective of this application is to advance novel peptide therapeutics for hypertension with a special
focus on resistant hypertension (RH) for which there are no approved drugs or devices in the US. Our
strategy is to target the particulate guanylyl cyclase receptor-A/cyclic guanosine monophosphate (pGC-
A/cGMP) pathway for which the cardiac hormone ANP is an endogenous ligand. Studies to date support a
key role for the pGC-A/cGMP pathway in blood pressure (BP) regulation. The mechanism of BP lowering is
natriuresis, vasodilation and aldosterone suppression. Beyond BP lowering properties, this pathway also
possesses anti-hypertrophic, anti-fibrotic, anti-inflammatory and endothelial protective actions. In the general
population, we and others have reported a genetic variation of the ANP gene (rs5068) is associated with higher
ANP, lower BP and protection from hypertension (HTN) and metabolic syndrome. We also reported that early
stages of human HTN are characterized by reduced ANP, while severe HTN is characterized by lower ANP
and higher aldosterone. Importantly, African Americans (AAs) represent an ethnic population at high risk for
RH and are characterized by a 40% reduction in circulating natriuretic peptides (NPs) compared to other ethnic
groups. The applicants designed MANP as a best-in-class pGC-A/cGMP activator, which possesses
enhanced pGC-A/cGMP activating properties, and is markedly resistant to degradation by neprilysin. In
experimental models, MANP is superior in lowering BP, enhancing natriuresis and suppressing aldosterone
compared to ANP. In the only human study to date, once daily subcutaneous injection of MANP, for three
days, in subjects with RH was well tolerated, safe and robustly reduced BP, suppressed aldosterone and
enhanced sodium excretion as well as GFR. First, we propose to define the responsiveness to MANP in
African Americans (AAs) with RH. Second, we will define the chronic cardiorenal protective and RAAS
suppressing actions of a next generation MANP (i.e. MANP2) in spontaneously hypertensive rats (SHRs).
Third, we propose to define synergism in vitro between two lead small molecule positive allosteric
modulators (PAMs) with MANP2 to optimize pGC-A activation. Specific Aim 1: Define BP, CV, renal,
neurohumoral, and cGMP responses of MANP in AAs with RH using Mayo Clinic's Center for Clinical and
Translational Science (CCaTS) Clinical Research Unit (CRU). Specific Aim 2: Establish in vivo the chronic
cardiorenal protective and RAAS suppressing properties of MANP2 in SHRs compared to Entresto. Specific
Aim 3: Define synergy in pGC-A/cGMP activation, in vitro, between two lead PAMs and MANP2 in human
primary cells.

## Key facts

- **NIH application ID:** 10077576
- **Project number:** 5R01HL136340-04
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** John C Burnett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $614,866
- **Award type:** 5
- **Project period:** 2018-03-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10077576

## Citation

> US National Institutes of Health, RePORTER application 10077576, Novel  Peptide Therapeutics for Hypertension (5R01HL136340-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10077576. Licensed CC0.

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