The
Kv1.3 potassium channel plays an essential role in effector memory T cells and has been implicated in several important
autoimmune diseases including
multiple sclerosis,
psoriasis and
type 1 diabetes. A number of potent small molecule inhibitors of Kv1.3 channel have been reported, some of which were found to be effective in various animal models of
autoimmune diseases. We report herein the identification of
clofazimine, a known anti-mycobacterial
drug, as a novel inhibitor of human Kv1.3.
Clofazimine was initially identified as an inhibitor of intracellular
T cell receptor-mediated signaling leading to the transcriptional activation of human
interleukin-2 gene in T cells from a screen of the Johns Hopkins
Drug Library. A systematic mechanistic deconvolution revealed that
clofazimine selectively blocked the Kv1.3 channel activity, perturbing the oscillation frequency of the
calcium-release activated calcium channel, which in turn led to the inhibition of the
calcineurin-NFAT signaling pathway. These effects of
clofazimine provide the first line of experimental evidence in support of a causal relationship between Kv1.3 and calcium oscillation in human T cells. Furthermore,
clofazimine was found to be effective in blocking human T cell-mediated skin graft rejection in an animal model in vivo. Together, these results suggest that
clofazimine is a promising immunomodulatory
drug candidate for treating a variety of autoimmune disorders.