KCNN4 as a Genomic Determinant of Cytosolic Delivery by the Attenuated Cationic Lytic Peptide L17E.

IF 12.1 1区医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Molecular Therapy Pub Date : 2025-01-01 DOI:10.1016/j.ymthe.2024.12.050

Masashi Kuriyama, Hisaaki Hirose, Yoshimasa Kawaguchi, Junya Michibata, Masashi Maekawa, Shiroh Futaki

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Abstract

The development of a cytosolic delivery strategy for biopharmaceuticals is one of the central issues in drug development. Knowledge of the mechanisms underlying these processes may also pave the way for the discovery of novel delivery systems. L17E is a an attenuated cationic amphiphilic lytic (ACAL) peptide developed by our research group that shows promise for cytosolic antibody delivery. In this study, given the high efficacy of L17E in cytosolic delivery, we investigated the mechanism of action of L17E in detail. L17E was found to achieve cytosolic delivery predominantly by transient disruption of the plasma membrane without the need for endocytosis. Importantly, the cell line selectivity studies of L17E revealed a strong correlation between the efficiency of L17E-mediated delivery and the expression level of KCNN4, the gene encoding the calcium-activated potassium channel KCa3.1. Genetic and pharmacological regulation of KCNN4 expression and KCa3.1 activity, respectively, correlate closely with the efficiency of L17E-mediated cytosolic delivery, suggesting the importance of membrane potential regulation by extracellular Ca²⁺ influx. Therefore, the activity of the L17E is relevant to the calcium-activated potassium channel.

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来源期刊

Molecular Therapy 医学-生物工程与应用微生物

CiteScore

19.20

自引率

3.20%

发文量

357

审稿时长

3 months

期刊介绍： Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.