ABCMdb

PMID: 24855632

Kirby EF, Heard AS, Wang XR
Enhancing the Potency of F508del Correction: A Multi-Layer Combinational Approach to Drug Discovery for Cystic Fibrosis.
J Pharmacol Clin Toxicol. 2013 Aug 28;1(1):1007., [PubMed]

Sentences

No. Mutations Sentence Comment

16 ABCC7 p.Gly551Asp Recently, the first such drug, ivacaftor, was approved by the U.S. Food and Drug Administration (FDA) to treat roughly 4% of CF patients that carry a G551D mutation in CFTR. Login to comment 42 ABCC7 p.Gly551Asp This latter approach led to the development of a potentiator (VX-770) that enhances the channel gating of CFTR carrying a G551D mutation [22]. Login to comment 43 ABCC7 p.Gly551Asp In 2012, VX-770 was approved by the U.S. FDA as an oral drug under the name of Kalydeco (ivacaftor) for treatment of CF patients six years or older, who carry the G551D mutant. Login to comment 64 ABCC7 p.Arg258Gly ABCC7 p.Ser945Leu ABCC7 p.His949Tyr VRT-325 was found to rescue not only F508del CFTR but also other CFTR processing mutants such as R258G, S945L, and H949Y, and processing mutants of P-glycoprotein (P-gp), a drug pump that also belongs to the ABC transporter family [29]. Login to comment 67 ABCC7 p.Arg555Lys ABCC7 p.Arg553Lys In contrast, combined second-site suppressor mutations R553K/R555K (2RK) in NBD1 not only alter the protease susceptibility of NBD1 but also that of other domains of F508del CFTR. Login to comment 84 ABCC7 p.His620Gln H620Q substitution at the C-terminal region of NBD1 is known to increase the channel open probability of CFTR [34]. Login to comment 86 ABCC7 p.His620Gln NMR studies of human F508del NBD1 either carrying the H620Q mutation or treated with CFFT-001 revealed a similar disruption of the interactions between the (b2;-strands S3, S9, and S10 and the C-terminal helices H8 and H9, suggesting a similar conformational shift [35]. Login to comment 87 ABCC7 p.His620Gln Differential scanning calorimetry showed a reduced Tm of NBD1 Kirby et al. Page 5 in the presence of H620Q or CFFT-001, suggesting that CFFT-001 binds to a less stable conformation of NBD1 [35]. Login to comment