# Mechanisms of Maladaptation in Heart Failure

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $754,528

## Abstract

Summary of Work
 G protein-coupled receptors (GPCRs) are one of the largest group of therapeutic targets in
cardiovascular disease. Ligands for GPCRs are characterized as agonists: those that stabilize
a receptor conformation that promote activation of heterotrimeric G-proteins to generate
second-messenger signaling; or antagonists such as β-blockers that block such activation.
While β-blockers are standard of therapy in heart failure, there is evidence for a positive
relationship between higher β-blocker dose and improved clinical outcomes. However,
achieving a maximal dose is often difficult due to the development of intolerable adverse effects.
Thus developing novel ligands that have improved efficacy and reduced untoward effects is a
huge unmet need.
 Studies over the past 2 decades, in a large part from investigators on this proposal, have
shown that orthosteric ligands, i.e. the binding site of the endogenous ligand, stabilize distinct
active receptor conformations to selectively engage either G-protein or β-arrestin, to induce
distinct signaling pathways. This concept of orthosteric ligand-dependent transducer selectivity
is known as biased signaling and has been shown to activate cardioprotective pathways. While
the majority of GPCR ligands target orthosteric binding sites, an emerging area of receptor
biology and drug development is the identification of ligands that bind to allosteric, or
topographically distinct, sites on receptors. Allosteric ligands that potentiate activity of
orthosteric agonists are termed positive allosteric modulators (PAMs), while those that
noncompetitively decrease the activity of orthosteric agonists are termed negative allosteric
modulators (NAMs). It is now apparent that allosteric ligands may offer great benefit as
therapeutics because of enhanced receptor specificity and efficacy.
 The objective of this R01 renewal is to identify, characterize, and translate newly identified
allosteric modulators on the β1 adrenergic receptor (β1AR) from our recently performed DNA-
encoded library (DEL) screen of 1 billion unique chemical entities with the ultimate goal of
identifying β-arrestin biased PAMs. To accomplish this ambitious goal, I have assembled a
team of experts in GPCR biology and organic chemistry that are known for innovative,
paradigm-shifting research. I propose the following specific aims.

## Key facts

- **NIH application ID:** 10889251
- **Project number:** 5R01HL056687-27
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Howard A Rockman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $754,528
- **Award type:** 5
- **Project period:** 1996-08-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10889251

## Citation

> US National Institutes of Health, RePORTER application 10889251, Mechanisms of Maladaptation in Heart Failure (5R01HL056687-27). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10889251. Licensed CC0.

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