Drug Discovery Opinion

Bz-423, a mitochondrial F₁F₀-ATP synthase inhibitor, that has previously shown promise for the treatment of autoimmune disorders such as lupus, arthritis and psoriasis has now been shown to halt the progression of established graft-versus-host disease (GVHD) in mouse models of allogeneic bone marrow transplantation. GVHD, in which functional immune cells in the transplanted marrow mount an immunological attack on the recipient, is a common complication of allogeneic bone marrow transplantation that can cause severe organ damage and even be life-threatening. As well as demonstrating that Bz-423 can reduce GVHD clinical scores and improve survival in mice, researchers at the University of Michigan and the University of Florida have shed new light on the metabolism of alloreactive T cells.

Resting lymphocytes meet their minimal demand for ATP using low rates of oxidative phosphorylation. Upon activation, normal lymphocytes meet the increased demand for ATP by dramatically increasing their rate of aerobic glycolysis which also helps to maintain high levels of antioxidants in activated cells. Data from the present study suggest that alloreactive T cells, on the other hand, rely heavily on increased oxidative phosphorylation to generate more ATP. This difference in energy generation is also seen in pathogenic T cells involved in autoimmune diseases and provides a mechanistic basis for the specific elimination of pathogenic cells by Bz-423, whilst preserving normal immune function.

The study is published in Science Translational Medicine.

Lycera Corporation has a program to develop orally bioavailable F₁F₀-ATP synthase inhibitors that exploit bioenergetic abnormalities in pathologically activated lymphocytes and result in the selective silencing of these cells.

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