# Peptibodies As Novel Therapies in Atrial Fibrillation

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2024 · $597,933

## Abstract

ABSTRACT
Atrial fibrillation (AF) is the most common arrhythmia and its prevalence is rising alarmingly. It is particularly challenging
to treat persistent AF and to restore normal sinus rhythm with currently available antiarrhythmics. Therefore, novel ion
channel blocking modalities are needed for the development of the next generation of antiarrhythmic pharmacotherapies in
persistent AF. A hallmark of remodeling in the chronically fibrillating atria is the presence of a constitutively active,
parasympathetic stimulation independent acetylcholine sensitive inward rectifier potassium current (IKACh). Constitutively
active IKACh acts as a background inward rectifier conductance and can contribute to the shortening of the atrial effective
refractory period, and consequently to the perpetuation of AF. We demonstrated earlier that IKACh blockade with the
peptidotoxin tertiapinQ, a 21-amino acid synthetic peptide blocker of IKACh originally isolated from the European honeybee
venom, terminates persistent AF. We thus bioengineered, produced and characterized a novel, and potent IKACh blocking
peptibody. Peptibodies are chimeras generated as fusion proteins of the fragment crystallizable (Fc) domain of the human
immunoglobulin G (IgG1) with a bioactive “warhead” peptide. Peptibodies combine the biologic/therapeutic activity of a
given peptide, with the stability of monoclonal antibodies and are stable and safe molecules that are emerging as viable
clinical therapies. Our IKACh blocking peptibody was constructed as a fusion protein between the Fc fragment of human IgG1
and tertiapinQ linked together by an octaglycine spacer. In this application, we propose to test the hypothesis that
bioengineered peptibodies designed as potent and bioactive blockers of IKACh are antiarrhythmic in persistent AF. Our goals
are: 1- to delineate the structural determinants for the peptibody’s block of IKACh; 2- to determine the atrial specificity,
electrophysiological safety and therapeutic potential of anti-IKACh peptibodies in a pig model of persistent AF; and 3- to
bioengineer next generation peptibodies that have increased IKACh potency and specificity. Successful accomplishment of
our proposal should be a major step forward in the deliberate, innovative, and rational development of much needed and
effective antifibrillatory agents based on bioengineering approaches that target ion channels important in the mechanism of
a major cardiac disease.

## Key facts

- **NIH application ID:** 10757751
- **Project number:** 5R01HL163943-02
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Jose S Jalife
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $597,933
- **Award type:** 5
- **Project period:** 2023-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757751

## Citation

> US National Institutes of Health, RePORTER application 10757751, Peptibodies As Novel Therapies in Atrial Fibrillation (5R01HL163943-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10757751. Licensed CC0.

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