Portal de Periódicos da CAPES

Correolide and Derivatives Are Novel Immunosuppressants Blocking the Lymphocyte Kv1.3 Potassium Channels

1999; Elsevier BV; Volume: 197; Issue: 2 Linguagem: Inglês

10.1006/cimm.1999.1569

1090-2163

Gloria C. Koo, Joseph T. Blake, Kashmira Shah, Mary Jo Staruch, Francis J. Dumont, Denise Wunderler, Manuel Sánchez, Owen B. McManus, Anna Sirotina-Meisher, Paul Fischer, Robert C. Boltz, Michael Goetz, Robert K. Baker, Jianming Bao, Frank Kayser, Kathleen M. Rupprecht, William H. Parsons, Xinchun Tong, Ida E. Ita, Jim Pivnichny, Stella Vincent, Paul Cunningham, D. F. Hora, William P. Feeney, Gregory J. Kaczorowski, Martin S. Springer,

Marine Sponges and Natural Products

The voltage-gated potassium channel, Kv1.3, is specifically expressed on human lymphocytes, where it controls membrane potential and calcium influx. Blockade of Kv1.3 channels by margatoxin was previously shown to prevent T cell activation and attenuate immune responses in vivo. In the present study, a triterpene natural product, correolide, was found to block Kv1.3 channels in human and miniswine T cells by electrophysiological characterization. T cell activation events, such as anti-CD3-induced calcium elevation, IL-2 production, and proliferation were inhibited by correolide in a dose-dependent manner. More potent analogs were evaluated for pharmacokinetic profiles and subsequently tested in a delayed-type hypersensitivity (DTH) response to tuberculin in the miniswine. Two compounds were dosed orally, iv, or im, and both compounds suppressed DTH responses, demonstrating that small molecule blockers of Kv1.3 channels can act as immunosuppressive agents in vivo. These studies establish correolide and its derivatives as novel immunosuppressants.