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Oscar Moran, Ph.D. - "Anion transport mechanisms through lipid bilayers by synthetic ionophores: towards a cystic fibrosis therapy"

Istituto di Biofisica, CNR, Genova, Italy
When Feb 06, 2018
from 12:00 PM to 01:30 PM
Where Tigem, Auditorium "Vesuvius"
Contact Name
Contact Phone 08119230659
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Abstract
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 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 characterised the mechanism of anion transport of synthetic molecules based on the structure of  prodigiosine, a red pigment produced by bacteria. Using ion sensitive electrodes (ISE), we measured the chloride eflux from large unilamelar liposomes upon addition of micromolar amounts of anionophores. Data is consistent with a carrier that facilitates the transport of anions  through lipid membranes down the electrochemical gradient. The transport is not coupled with proton or hydroxide translocations. The selectivity sequence of the prodigiosin inspired ionophores is formate > acetate > nitrate > chloride >  bicarbonate. Sulphate, phosphate, aspartate and gluconate are virtually not transported by these anionophores. The transport activity is modulated by the pH at the side where the anionophore is applied, suggesting that the ionization state of the molecule may decide the anion-anionophore interaction. These prodigiosin-derivate ionophores can also induce anion transport in living cells. Their capacity to transport chloride and bicarbonate when applied at low concentration, and  low toxicity take shape as a promising starting point for the development of CF-therapy drug candidates.

The project TAT-CF has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 667079

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