Abstract

Membrane proteins constitute a substantial fraction of the human proteome, thus representing a vast source of therapeutic drug targets. Indeed, newly devised technologies now allow targeting “undruggable” regions of membrane proteins to modulate protein function in the cell. Despite the advances in technology, the rapid translation of basic science discoveries into potential drug candidates targeting transmembrane protein domains remains challenging. We address this issue by harmonizing single molecule-based and ensemble-based atomistic simulations of ligand–membrane interactions with patient-derived induced pluripotent stem cell (iPSC)-based experiments to gain insights into drug delivery, cellular efficacy, and safety of molecules directed at membrane proteins. In this study, we interrogated the pharmacological activation of the cardiac Ca2+ pump (Sarcoplasmic reticulum Ca2+-ATPase, SERCA2a) in human iPSC-derived cardiac cells as a proof-of-concept model. The combined computational-experimental approach serves as a platform to explain the differences in the cell-based activity of candidates with similar functional profiles, thus streamlining the identification of drug-like candidates that directly target SERCA2a activation in human cardiac cells. Systematic cell-based studies further showed that a direct SERCA2a activator does not induce cardiotoxic pro-arrhythmogenic events in human cardiac cells, demonstrating that pharmacological stimulation of SERCA2a activity is a safe therapeutic approach targeting the heart. Overall, this novel multiscale platform encompasses organ-specific drug potency, efficacy, and safety, and opens new avenues to accelerate the bench-to-patient research aimed at designing effective therapies directed at membrane protein domains.

Highlights

  • Membrane proteins constitute a substantial fraction of the human proteome, representing a vast source of therapeutic drug targets

  • It is important to note that other small molecules have been reported to activate SERCA2a; these effects are indirect

  • These findings indicate that these molecules are relatively potent toward SERCA2a, with average ­EC50 values in the low μM range

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Summary

Introduction

Membrane proteins constitute a substantial fraction of the human proteome, representing a vast source of therapeutic drug targets. Systematic cell-based studies further showed that a direct SERCA2a activator does not induce cardiotoxic pro-arrhythmogenic events in human cardiac cells, demonstrating that pharmacological stimulation of SERCA2a activity is a safe therapeutic approach targeting the heart Overall, this novel multiscale platform encompasses organ-specific drug potency, efficacy, and safety, and opens new avenues to accelerate the bench-to-patient research aimed at designing effective therapies directed at membrane protein domains. Understanding the relationships between target-based potency and cell-based efficacy is of utmost importance to accelerate the discovery and development of biologically active molecules targeting transmembrane protein domains To address this issue, here we used complementary single-molecule and ensemble-based atomistic simulations of lipid–ligand interaction, in situ enzymatic activity assays, and highresolution optical mapping using human iPSC-derived cardiac cells to systematically interrogate pharmacological modulation of SERCA2a activation as a model. The result is a comprehensive platform that encompasses drug delivery, target engagement, cellular efficacy, and safety of molecules directed at membrane proteins

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