# A full spectrum rational approach to identify antiarrhythmic agents targeting IKs Channels

> **NIH HL R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2026 · $656,747

## Abstract

Project Summary
Acquired Long Q-T Syndrome (aLQTS) is a change in the electrocardiogram (EKG) due to lengthening of the
ventricular electrical event, the action potential (AP). This lengthened AP predisposes to a lethal arrhythmia
and sudden death. aLQTS is induced by many drugs approved by the FDA. However, the approved doses are
limited by this side effect. The slow delayed rectifier, IKs, is a K+ current that can prevent aLQTS by shortening
the APD. This proposal focuses on developing candidate agents that can eliminate the APD prolongation
induced by drugs that cause aLQTS. There are 5 steps that regulate opening of the channel, voltage sensor
activation, phosphatidylinositol 4,5-biphosphate (PIP2), Calmodulin, ATP and opening of the pore. Two of
these, voltage sensor activation and PIP2 binding, have led us to two candidate compounds for aLQTS.
Because many drug candidates fail due to cardiac toxicity, it is important to investigate all mechanisms
controlling channel opening. The first aim, Aim 1, investigates how calmodulin and ATP binding and pore
opening can be stimulated by novel agents to increase IKs. The systematic process by which the selection of
these novel agents is achieved is called Full Spectrum Rational Drug Design. The structure of the channel is
studied and the binding sites for compounds to modify particular steps in channel opening are determined
(e.g., calmodulin and ATP interactions and pore opening). A computer program uses this structural information
to screen a chemical library of more than 1 million compounds for those most likely to bind near to the
structurally defined site. Multiple compounds have already been identified as potentially effective and
preliminary data are provided from these compounds for each potential site. Aim 1 tests these compounds to
determine their action on IKs, as well as their dose response curve and selectivity. The proposed mechanistic
studies of each therapeutic site will provide insight into any antiarrhy

## Key facts

- **NIH application ID:** 11349666
- **Project number:** 5R01HL166628-04
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Jianmin  Cui; RICHARD Z LIN; XIAOQIN  ZOU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** HL
- **Fiscal year:** 2026
- **Award amount:** $656,747
- **Award type:** 5
- **Project period:** 2023-07-01T00:00:00 → 2027-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11349666

## Citation

> US National Institutes of Health, RePORTER application 11349666, A full spectrum rational approach to identify antiarrhythmic agents targeting IKs Channels (5R01HL166628-04). Retrieved via AI Analytics 2026-07-14 from https://api.ai-analytics.org/grant/nih/11349666. Licensed CC0.

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