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Modulation of Lymphocyte Potassium Channel K_V1.3 by Membrane-Penetrating, Joint-Targeting Immunomodulatory Plant Defensin.

ABSTRACT: We describe a cysteine-rich, membrane-penetrating, joint-targeting, and remarkably stable peptide, EgK5, that modulates voltage-gated K_V1.3 potassium channels in T lymphocytes by a distinctive mechanism. EgK5 enters plasma membranes and binds to K_V1.3, causing current run-down by a phosphatidylinositol 4,5-bisphosphate-dependent mechanism. EgK5 exhibits selectivity for K_V1.3 over other channels, receptors, transporters, and enzymes. EgK5 suppresses antigen-triggered proliferation of effector memory T cells, a subset enriched among pathogenic autoreactive T cells in autoimmune disease. PET-CT imaging with ¹⁸F-labeled EgK5 shows accumulation of the peptide in large and small joints of rodents. In keeping with its arthrotropism, EgK5 treats disease in a rat model of rheumatoid arthritis. It was also effective in treating disease in a rat model of atopic dermatitis. No signs of toxicity are observed at 10-100 times the in vivo dose. EgK5 shows promise for clinical development as a therapeutic for autoimmune diseases.

SUBMITTER: Ong ST

PROVIDER: S-EPMC7432667 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Modulation of Lymphocyte Potassium Channel KV1.3 by Membrane-Penetrating, Joint-Targeting Immunomodulatory Plant Defensin.

Ong Seow Theng ST Bajaj Saumya S Tanner Mark R MR Chang Shih Chieh SC Krishnarjuna Bankala B Ng Xuan Rui XR Morales Rodrigo A V RAV Chen Ming Wei MW Luo Dahai D Patel Dharmeshkumar D Yasmin Sabina S Ng Jeremy Jun Heng JJH Zhuang Zhong Z Nguyen Hai M HM El Sahili Abbas A Lescar Julien J Patil Rahul R Charman Susan A SA Robins Edward G EG Goggi Julian L JL Tan Peng Wen PW Sadasivam Pragalath P Ramasamy Boominathan B Hartimath Siddana V SV Dhawan Vikas V Bednenko Janna J Colussi Paul P Wulff Heike H Pennington Michael W MW Kuyucak Serdar S Norton Raymond S RS Beeton Christine C Chandy K George KG

ACS pharmacology & translational science 20200514 4

We describe a cysteine-rich, membrane-penetrating, joint-targeting, and remarkably stable peptide, EgK5, that modulates voltage-gated KV1.3 potassium channels in T lymphocytes by a distinctive mechanism. EgK5 enters plasma membranes and binds to KV1.3, causing current run-down by a phosphatidylinositol 4,5-bisphosphate-dependent mechanism. EgK5 exhibits selectivity for KV1.3 over other channels, receptors, transporters, and enzymes. EgK5 suppresses antigen-trigge ...[more]

PMID: 32832873

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Project description:BackgroundIon channels are emerging as promising oncological targets. The potassium channels Kv1.3 and IKCa are highly expressed in the plasma membrane and mitochondria of human chronic lymphocytic leukemia (CLL) cells, compared to healthy lymphocytes. In vitro, inhibition of mitoKv1.3 by PAPTP was shown to kill ex vivo primary human CLL cells, while targeting IKCa with TRAM-34 decreased CLL cell proliferation.MethodsHere we evaluated the effect of the above drugs in CLL cells from ibrutinib-resistant patients and in combination with Venetoclax, two drugs used in the clinical practice. The effects of the drugs were tested also in the Eμ-TCL1 genetic CLL murine model, characterized by a lympho-proliferative disease reminiscent of aggressive human CLL. Eμ-TCL1 mice showing overt disease state were treated with intraperitoneal injections of non-toxic 5 nmol/g PAPTP or 10 nmol/g TRAM-34 once a day and the number and percentage of pathological B cells (CD19+CD5+) in different, pathologically relevant body districts were determined.ResultsWe show that Kv1.3 expression correlates with sensitivity of the human and mouse neoplastic cells to PAPTP. Primary CLL cells from ibrutinib-resistant patients could be killed with PAPTP and this drug enhanced the effect of Venetoclax, by acting on mitoKv1.3 of the inner mitochondrial membrane and triggering rapid mitochondrial changes and cytochrome c release. In vivo, after 2 week- therapy of Eμ-TCL1 mice harboring distinct CLL clones, leukemia burden was reduced by more than 85%: the number and percentage of CLL B cells fall in the spleen and peritoneal cavity and in the peripheral blood, without signs of toxicity. Notably, CLL infiltration into liver and spleen and splenomegaly were also drastically reduced upon PAPTP treatment. In contrast, TRAM-34 did not exert any beneficial effect when administered in vivo to Eμ-TCL1 mice at non-toxic concentration.ConclusionAltogether, by comparing vehicle versus compound effect in different Eμ-TCL1 animals bearing unique clones similarly to CLL patients, we conclude that PAPTP significantly reduced leukemia burden in CLL-relevant districts, even in animals with advanced stage of the disease. Our results thus identify PAPTP as a very promising drug for CLL treatment, even for the chemoresistant forms of the disease.

Dataset Information

Modulation of Lymphocyte Potassium Channel K_V1.3 by Membrane-Penetrating, Joint-Targeting Immunomodulatory Plant Defensin.

Publications

Modulation of Lymphocyte Potassium Channel K<sub>V</sub>1.3 by Membrane-Penetrating, Joint-Targeting Immunomodulatory Plant Defensin.

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