V-ATPases as drug targets

V-ATPases are large, complex enzymes responsible for acidification of many internal compartments in eukaryotic cells. They also occur oil plasma membranes,of specialized cells, where they acidify the Surrounding Milieu. Numerous physiological processes depend oil the activity of V-ATPases, and V-ATPases are implicated as a contributing factor in multiple diseases, including osteoporosis, deafness, and cancer. Three classes of natural products have been identified as potent inhibitors of V-ATPases. The bafilomycins and cocanamycins, which inhibit all known eukaryotic V-ATPascs, are the most extensively Studied inhibitors. They bind the V-0 subunit c and may inhibit the enzyme by preventing rotation of the c Subunit ring. The salicylihalamides and lobatamides show remarkable specificity for animal V-ATPases. The chondropsins preferentially inhibit the fungal V-ATPase. Because of the variety of processes and diseases associated with V-ATPases and the possibility of designing selective inhibitors, the V-ATPases are attractive targets for development of therapeutic agents.