Vacuolar ATPase as a drug discovery target.

Vacuolar ATPases (V-ATPases) are present not only in the plasma membranes of specialized cells but also in ubiquitous intracellular acidic compartments, which are essential for physiological cellular function. Consequently, although V-ATPases are important etiologically in several diseases, it seems that they might not be good molecular targets. In fact, bafilomycin A1, a potent and specific inhibitor of V-ATPase, exerts severe and acute toxic reaction when administered to animals. On the other hand, disruption of subunit a3 of V-ATPase is not embryonic lethal, but knockout mice merely exhibit osteopetrosis due to loss of osteoclastic bone resorption. In addition, recent studies have demonstrated that novel V-ATPase inhibitors, which have inhibition selectivity, can be systemically administered to animals and are highly efficacious against bone loss in lytic bone disease models. Therefore, the key issue regarding the therapeutic usefulness of V-ATPase inhibitors is their selectivity in the inhibition.