Discovery and validation of new Hv1 proton channel inhibitors with onco-therapeutic potential

Article Article scientifique Article Discovery and validation of new Hv1 proton channel inhibitors with onco-therapeutic potential eng 2023-01-12 2023-03 author Chemaly Antoine 651202 author Jaquet Vincent 639300 author Cambet Yves Alexandre 33476 author Caillon Aurélie 126300 author Cherpin Ophelie 688238 author Balafa Alexia 927998 author Krause Karl-Heinz 23022 author Demaurex Nicolas 0000-0002-9933-6772 24642 119415 10.1016/j.bbamcr.2022.119415 36640925 0167-4889 The voltage-gated hydrogen channel Hv1 encoded in humans by the HVCN1 gene is a highly selective proton channel that allows large fluxes of protons across biological membranes. Hv1 form functional dimers of four transmembrane spanning proteins resembling the voltage sensing domain of potassium channels. Each subunit is highly selective for protons and is controlled by changes in the transmembrane voltage and pH gradient. Hv1 is most expressed in phagocytic cells where it sustains NADPH oxidase-dependent bactericidal function and was reported to facilitate antibody production by B cells and to promote the maturation and motility of spermatocytes. Hv1 contributes to neuroinflammation following brain damage and favors cancer progression possibly by extruding protons generated during aerobic glycolysis of cancer cells. Lack of specific Hv1 inhibitors has hampered translation of this knowledge to treat immune, fertility, or malignancy diseases. In this study, we show that the genetic deletion of Hv1 delays tumor development in a mouse model of granulocytic sarcoma and report the discovery and characterization of two novel bioavailable inhibitors of Hv1 channels that we validate by orthogonal assays and electrophysiological recordings. Cancer Ion channels Oxidases Pharmacology Screening PH homeostasis Male Mice Animals Humans Ion Channels / genetics Ion Channels / metabolism Protons Cell Membrane / metabolism NADPH Oxidases / metabolism Phagocytes / metabolism Dewey 612 Dewey 616.07 137 Département de pathologie et immunologie 21F 134 Département de physiologie cellulaire et métabolisme 21C false 38 Radicaux libres et cellules souches embryonnaires 60 168 Signaux intracellulaires 210 Biochimica et biophysica acta. Molecular cell research 1870 3 10ba3c39-8e73-4a65-abab-94fd7ef20aba Article (Published version) Public 1-s2.0-S0167488922002075-main.pdf 2510291 application/pdf CC BY-4.0 openAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme

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Discovery and validation of new Hv1 proton channel inhibitors with onco-therapeutic potential	Biochimica et biophysica acta. Molecular cell research			2023	241	165

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Balafa, Alexia