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Reengineering an Antiarrhythmic Drug Using Patient hiPSC Cardiomyocytes to Improve Therapeutic Potential and Reduce Toxicity.

ABSTRACT: Modeling cardiac disorders with human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes is a new paradigm for preclinical testing of candidate therapeutics. However, disease-relevant physiological assays can be complex, and the use of hiPSC-cardiomyocyte models of congenital disease phenotypes for guiding large-scale screening and medicinal chemistry have not been shown. We report chemical refinement of the antiarrhythmic drug mexiletine via high-throughput screening of hiPSC-CMs derived from patients with the cardiac rhythm disorder long QT syndrome 3 (LQT3) carrying SCN5A sodium channel variants. Using iterative cycles of medicinal chemistry synthesis and testing, we identified drug analogs with increased potency and selectivity for inhibiting late sodium current across a panel of 7 LQT3 sodium channel variants and suppressing arrhythmic activity across multiple genetic and pharmacological hiPSC-CM models of LQT3 with diverse backgrounds. These mexiletine analogs can be exploited as mechanistic probes and for clinical development.

SUBMITTER: McKeithan WL

PROVIDER: S-EPMC7655512 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Therapeutic proteins are yielding ever more advanced and efficacious new drugs, but the biological origins of these highly effective therapeutics render them subject to immune surveillance within the patient's body. When recognized by the immune system as a foreign agent, protein drugs elicit a coordinated response that can manifest a range of clinical complications including rapid drug clearance, loss of functionality and efficacy, delayed infusion-like allergic reactions, more serious anaphylactic shock, and even induced auto-immunity. It is thus often necessary to deimmunize an exogenous protein in order to enable its clinical application; critically, the deimmunization process must also maintain the desired therapeutic activity.To meet the growing need for effective, efficient, and broadly applicable protein deimmunization technologies, we have developed the EpiSweep suite of protein design algorithms. EpiSweep seamlessly integrates computational prediction of immunogenic T cell epitopes with sequence- or structure-based assessment of the impacts of mutations on protein stability and function, in order to select combinations of mutations that make Pareto optimal trade-offs between the competing goals of low immunogenicity and high-level function. The methods are applicable both to the design of individual functionally deimmunized variants as well as the design of combinatorial libraries enriched in functionally deimmunized variants. After validating EpiSweep in a series of retrospective case studies providing comparisons to conventional approaches to T cell epitope deletion, we have experimentally demonstrated it to be highly effective in prospective application to deimmunization of a number of different therapeutic candidates. We conclude that our broadly applicable computational protein design algorithms guide the engineer towards the most promising deimmunized therapeutic candidates, and thereby have the potential to accelerate development of new protein drugs by shortening time frames and improving hit rates.

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Reengineering an Antiarrhythmic Drug Using Patient hiPSC Cardiomyocytes to Improve Therapeutic Potential and Reduce Toxicity.

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