Question

Briefly explain what each of these drugs (aminoglycosides, potentiators and correctors) are, how they work, and their advantages (or not) for working against specific CFTR mutation classes. (9 marks, 3-4 sentences for each
therapy)

b. Briefly describe what a CFTR potentiator is, and what conditions the CFTR protein must meet
in order for Ivacaftor (VX-770) to work.

c. Which of these would you recommend for an individuals  doctor to consider for his treatment iif the individual has mutation W1282X?
Include in your answer any drawbacks from these therapies that should be considered, and
if there is one specific treatment that may provide more benefit than the others.

Answer 1

Aminoglycosides are bactericidal antibiotics such as gentamicin, amikacin, tobramycin, neomycin, and streptomycin. They are commonly used for those children who has infection caused by Gram-negative pathogens. Aminoglycosides can be used for treatment of severe infections of the abdomen and urinary tract, bacteremia, endocarditis and prophylaxis. Their main function is to inhibit protein sysnthesis, it binds to the 30s ribosomal sub-unit and cause a misreading of the genetic code which leads to the interruption of normal bacterial protein synthesis. Some of the disadvantages of aminoglycosides against CFTR mutation are they can cause organ damage eg. ototoxic damage, vestibulo-toxic impairments, nephrotoxicity and encephalopathy. Some side-effects are loss of hearing, skin rashes, drowsiness etc.

A potentiator can catalyses the sensitization of an antigen. They are mainly to enhance agglutination and thereby detecting antibodies or antigens in a patient's blood sample. Some examples are albumin, LISS and PEG. Hydroxyzine or dextromethorphan potentiator is used for pain relieving.

b) CFTR helps in regulation of water and salt movement across epithelium-lining tissues. CFTR mutants can be constructed using QuikChange XL kit. CFTR encodes a phosphorylation-activated and adenosine triphosphate gated chloride channel.

It was observed that a CFTR potentiator, GLPG1837 has higher efficacy than ivacaftor for the G551D mutation. GLPG1837 and VX-770 potentiate CFTR gating in a similar way even though they have potency and efficacy differences. They are independent of nucleotide-binding domain (NBD) dimerization and ATP hydrolysis, the critical steps required for controlling CFTR’s gate opening and closing. While applying the two reagents together, it has shown that GLPG1837 and VX-770 are compete for the same site. The root cause of the disease cystic fibrosis (CF) is the loss of function mutations in the CFTR gene. Like other transporters, CFTR provide two transmembrane domains that has made the chloride permeation pathway and two cytosolic nucleotide binding domains. These two domains are NBD1 and NBD2  where CFTR’s ligand ATP binds to gate the channel. Moreover, CFTR has a unique regulatory domain which has multiple serine residues for PKA-dependent phosphorylation. When the R domain becomes phosphorylated, the gating of CFTR can be driven by ATP binding which induced NBD dimerization and hydrolysis draw out partial separation of the NBD dime.  VX-770 is used for the treatment of CF and for mutations because it has shown that VX-770 potentiates the activity of a variety of CFTR mutants with gating abnormalities. However prolonged exposure of VX-770 may have negative impacts on the action of VX-809. Hence, CFTR potentiators play an inportant role in pharmacological improvement.