ATP6V0E1 Inhibitors

The inhibitors targeting ATP6V0E1 span a spectrum of mechanisms centered on compromising the protein's capacity to maintain proton gradients across cellular compartments. Concanamycin A is a specific V-ATPase inhibitor that operates by halting proton transport directly, thereby directly crippling ATP6V0E1's role in these processes. These inhibitors target the catalytic subunits of the V-ATPase complex, leading to direct inhibition. Azithromycin and Chloroquine work by altering lysosomal pH, thereby indirectly influencing the protein. These compounds accumulate in lysosomes, and their influence on pH levels results in impaired V-ATPase functionality, affecting ATP6V0E1 as a consequence.

Other inhibitors like Nigericin and FCCP introduce changes in membrane proton gradients by other means. Nigericin functions as an H+/K+ antiporter that negates the proton gradient, thus stalling ATP6V0E1's activity. FCCP acts as an uncoupler in oxidative phosphorylation, leading to a generalized disruption in proton gradients across various membranes, including those where ATP6V0E1 operates. Salicylihalamide A and DCC directly target the proton transport activity of the protein. Salicylihalamide A inhibits V-ATPase by the transport of protons across intracellular compartments, while DCCD covalently modifies the protein to render it inactive. Apilimod and YM201636 work through inhibiting PIKfyve kinase, leading to a domino effect that culminates in disrupted vesicle acidification or endosomal trafficking, which then hampers the functionality of ATP6V0E1 in these pathways.