A multiscale approach for bridging the gap between potency, efficacy, and safety of small molecules directed at membrane proteins.

Autor: Aguayo-Ortiz R; Division of Cardiovascular Medicine, Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI, 48109, USA.; Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, 04510, Mexico, Mexico., Creech J; Division of Cardiovascular Medicine, Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI, 48109, USA.; Frankel Cardiovascular Regeneration Core Laboratory, University of Michigan, Ann Arbor, MI, 48109, USA., Jiménez-Vázquez EN; Division of Cardiovascular Medicine, Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI, 48109, USA.; Department of Pharmacology, University of Michigan, Ann Arbor, MI, 48109, USA., Guerrero-Serna G; Division of Cardiovascular Medicine, Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI, 48109, USA., Wang N; Division of Cardiovascular Medicine, Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI, 48109, USA., da Rocha AM; Division of Cardiovascular Medicine, Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI, 48109, USA.; Frankel Cardiovascular Regeneration Core Laboratory, University of Michigan, Ann Arbor, MI, 48109, USA., Herron TJ; Division of Cardiovascular Medicine, Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI, 48109, USA.; Frankel Cardiovascular Regeneration Core Laboratory, University of Michigan, Ann Arbor, MI, 48109, USA.; CARTOX, Inc., 56655 Grand River Ave., PO Box 304, New Hudson, MI, 48165, USA., Espinoza-Fonseca LM; Division of Cardiovascular Medicine, Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI, 48109, USA. lmef@umich.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2021 Aug 16; Vol. 11 (1), pp. 16580. Date of Electronic Publication: 2021 Aug 16.
DOI: 10.1038/s41598-021-96217-7
Abstrakt: 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 Ca 2+ pump (Sarcoplasmic reticulum Ca 2+ -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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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