Discovery of Novel Human
Aquaporin‑1 Blockers
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Abstract
Human aquaporin-1 (hAQP1) is a water channel found in
many tissues
and potentially involved in several human pathologies. Selective inhibitors
of hAQP1 are discussed as novel treatment opportunities for glaucoma,
brain edema, inflammatory pain, and certain types of cancer. However,
only very few potent and chemically attractive blockers have been
reported to date. In this study we present three novel hAQP1 blockers
that have been identified by virtual screening and inhibit water flux
through hAQP1 in <i>Xenopus laevis</i> oocyte swelling assays
at low micromolar concentrations. The newly discovered compounds display
no chemical similarity to hitherto known hAQP1 blockers and bind at
the extracellular entrance of the channel, close to the ar/R selectivity
filter. Futhermore, mutagenesis studies showed that Lys36, which is
not conserved among the hAQP family, is crucially involved in binding
and renders the discovered compounds suitable as leads for the development
of selective hAQP1 inhibitors