# Mechanisms and discovery of small-molecule effectors targeting cardiac ion pumps

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $591,090

## Abstract

PROJECT SUMMARY/ABSTRACT
The overarching goal of our proposed research is to determine the mechanisms underlying small-molecule
activation of the cardiac calcium pump (sarcoplasmic reticulum Ca2+-ATPase, SERCA), and the discovery of
new classes of small-molecule inhibitors of the cardiac sodium pump (Na+/K+-ATPase, NKA). SERCA and NKA
play a key role in the excitation-contraction-relaxation cycle in normal and pathological cardiac muscle and are
validated pharmacological targets for heart failure (HF) therapies. Therefore, drug discovery and development
targeting these pumps unlock exciting new opportunities for developing HF therapies that are directed at the
heart. However, challenges limit drug discovery efforts targeting these ion pumps: (1) Despite the tremendous
advances in crystallography and cryo-EM, there are no structures of SERCA bound to small-molecule activators,
so the structural mechanisms for small-molecule activation of SERCA are still unclear; (2) Existing sodium pump
modulators are primarily cardiotonic steroids that have a narrow therapeutic window and pro-arrhythmia
cardiotoxic effects at therapeutically relevant doses. To overcome these challenges, we will use experimental
and computational approaches to determine the structural mechanisms for small-molecule activation of SERCA
and to discover new non-cardiotoxic, lead-like inhibitors of NKA. The proposal is significant because it will
produce new mechanistic insights and small-molecule effectors targeting two major clinically relevant targets
in the heart. The research is translational because it will expedite the discovery of lead molecules targeting
cardiac pumps. We will pursue the following independent aims: (1) Determine the mechanisms and interactions
for small-molecule SERCA activators, and (2) Discover novel non-cardiotoxic NKA inhibitors for congestive heart
failure. We have performed preliminary studies that show the feasibility of the proposed research, including
fresh evidence showing that small-molecule SERCA activation involves both a structural and a kinetic
mechanism, and the discovery of a novel potent NKA inhibitor with a safe pro-arrhythmia cardiac toxicity profile.

## Key facts

- **NIH application ID:** 10994836
- **Project number:** 1R01HL176212-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Lennane Michel Espinoza-Fonseca
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $591,090
- **Award type:** 1
- **Project period:** 2024-09-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10994836

## Citation

> US National Institutes of Health, RePORTER application 10994836, Mechanisms and discovery of small-molecule effectors targeting cardiac ion pumps (1R01HL176212-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10994836. Licensed CC0.

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