Correolide and derivatives are novel immunosuppressants blocking the lymphocyte Kv1.3 potassium channels.
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.
Koo
G C
GC
Merck Research Laboratories, Rahway, New Jersey, 07065, USA.
Blake
J T
JT
Shah
K
K
Staruch
M J
MJ
Dumont
F
F
Wunderler
D
D
Sanchez
M
M
McManus
O B
OB
Sirotina-Meisher
A
A
Fischer
P
P
Boltz
R C
RC
Goetz
M A
MA
Baker
R
R
Bao
J
J
Kayser
F
F
Rupprecht
K M
KM
Parsons
W H
WH
Tong
X C
XC
Ita
I E
IE
Pivnichny
J
J
Vincent
S
S
Cunningham
P
P
Hora
D
D
Feeney
W
W
Kaczorowski
G
G
D000818:Animals; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology*; D015640:Ion Channel Gating; D051664:Kv1.3 Potassium Channel; D015394:Molecular Structure; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013552:Swine; D013556:Swine, Miniature; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*
D007166:Immunosuppressive Agents; C496973:KCNA3 protein, human; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D014315:Triterpenes; C118657:correolide