Cystic fibrosis (CF) is a genetic lethal disease, originated from the defective function
of the CFTR protein, a chloride and bicarbonate permeable transmembrane channel.
CF mutations affect CFTR protein through a variety of molecular mechanisms which
result in different functional defects. Current therapeutic approaches are targeted to
specific groups of patients that share a common functional defect. We seek to develop
an innovative therapeutic approach for the treatment of CF using anionophores, small
molecules that facilitate the transmembrane transport of anions. We have characterized
the anion transport mechanism of a synthetic molecule based on the structure of
prodigiosine, a red pigment produced by bacteria. Anionophore-driven chloride efflux
from large unilamellar vesicles is consistent with activity of an uniporter carrier that
facilitates the transport of anions through lipid membranes down the electrochemical
gradient. There are no evidences of transport coupling with protons. The selectivity
sequence of the prodigiosin inspired EH160 ionophore is formate > acetate > nitrate
> chloride > bicarbonate. Sulfate, phosphate, aspartate, isothionate, and gluconate are
not significantly transported by these anionophores. Protonation at acidic pH is important
for the transport capacity of the anionophore. This prodigiosin derived ionophore induces
anion transport in living cells. Its low toxicity and capacity to transport chloride and
bicarbonate, when applied at low concentration, constitute a promising starting point
for the development of drug candidates for CF therapy.
