NDLI: Rescue of Folding Defects in ABC Transporters Using Pharmacological Chaperones

Content Provider	Springer Nature Link
Author	Loo, Tip W. Bartlett, M. Claire Clarke, David M.
Copyright Year	2005
Abstract	The ATP-binding cassette (ABC) family of membrane transport proteins is the largest class of transporters in humans (48 members). The majority of ABC transporters function at the cell surface. Therefore, defective folding and trafficking of the protein to the cell surface can lead to serious health problems. The classic example is cystic fibrosis (CF). In most CF patients, there is a deletion of Phe508 in the CFTR protein (ΔF508 CFTR) that results in defective folding and intracellular retention of the protein (processing mutant). A potential treatment for most patients with CF would be to use a ligand(s) of CFTR that acts a pharmacological chaperone to correct the folding defect. The feasibility of such an approach was first demonstrated with the multidrug transporter P-glycoprotein (P-gp), an ABC transporter, and a sister protein of CFTR. It was found that P-gps with mutations at sites equivalent to those found in CFTR processing mutants were rescued when they were expressed in the presence of drug substrates or modulators of P-gp. These compounds acted as pharmacological chaperones and functioned by promoting interactions among the various domains in the protein during the folding process. Several groups have attempted to identify compounds that could rescue the folding defect in ΔF508 CFTR. The best compound identified through high-throughout screening is a quinazoline derivative (CFcor-325). Expression of ΔF508 CFTR as well as other CFTR processing mutants in the presence of 1 μM CFcor-325 promoted folding and trafficking of the mutant proteins to the cell surface in an active conformation. Therefore, CFcor-325 and other quinazoline derivates could be important therapeutic compounds for the treatment of CF.
Starting Page	501
Ending Page	507
Page Count	7
File Format	PDF
ISSN	0145479X
Journal	Journal of Bioenergetics and Biomembranes
Volume Number	37
Issue Number	6
e-ISSN	15736881
Language	English
Publisher	Kluwer Academic Publishers-Plenum Publishers
Publisher Date	2005-01-01
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Cystic fibrosis CFTR pharmacological chaperones drug rescue P-glycoprotein protein misfolding Organic Chemistry Biochemistry Animal Biochemistry Animal Anatomy / Morphology / Histology Bioorganic Chemistry
Content Type	Text
Resource Type	Article
Subject	Cell Biology Physiology

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