Cystic Fibrosis Med Chem

Week 13 -> Dr. Ghoneim

What is cystic fibrosis?

A chronic disease of the airways/autosomal recessive genetic disorder characterized by a mutation in the CFTR protein.

What is the CFTR protein responsible for?

Chloride (Cl) transport across membranes to the lungs

What is the common mutation in CFTR?

F508del

• Deletion in the amino acid phenylalanine at position 508, resulting in impaired production of the CFTR protein

What happens as a result of the defect in CFTR gene?

• Decreased secretion of Cl-

• Increased reabsorption of Na⁺ into cellular space

What is salty sweat?

People with CF often sweat more than those without this condition; this particular sweat contains high levels of chloride, which can crystallize into salt that’s visible on the skin.

Decreased Cl- secretion & uncontrolled Na⁺ reabsorption results in what?

Dehydrated Airway Surface Liquid → defective mucous clearance

What is the goal of CF treatment?

Optimizing function to avoid acute illness events

Pulmonary pharmacological treatment

• Reduce the mucus

• Treat the infection (Azithromycin)

• Improve oxygenation/ventilation (SABA)

• Reduce exacerbations

• Airway clearance (Dornase alpha)

What are the types of pharmacological treatment available for CF?

• Beta agonists (i.e., SABA)

• CFTR modulators

• Dornase alpha

• Antibiotics

• Supplementals

β₂-selective agonists for CF treatment

Short-acting; clears the airway

• e.g., Albuterol, Levalbuterol, Terbutaline

• Rapid onset: 5 minutes

• DOA: 3-4 hours

What are the 2 types of CFTR modulators (i.e., “-caftor”)?

Potentiators and Correctors

Example of CFTR potentiator

Ivacaftor (Kalydeco)

Examples of CFTR correctors

• Lumacaftor

• Lumacaftor and Ivacaftor

• Tezacaftor and Ivacaftor

Ivacaftor (Kalydeco)

MOA: CFTR potentiator

• Increases flow of ions through activated CFTR present at the cell surface

• Allows the opening probability of the channel to be increased

• (i.e., enable opening of what would otherwise be a dysfunctional chloride channel)

• Some Cl- and Na⁺ going out of the cell

Lumacaftor and Tezacaftor

MOA: CFTR corrector

• Corrects the structure of CFTR after the F508del mutation

• Increases the trafficking of CFTR proteins to outer membrane

• Channel opens even more → increased Cl- going out

• CYP3A4 inducer, CYP2B6 inducer, CYP2C19 inhibitor, P-gp inhibitor

• Tezacaftor brings more CFTR proteins to the cell surface

• Ivacaftor helps CFTR proteins stay open longer at the cell surface

Lumacaftor/Ivacaftor (Orkambi)

• Lumacaftor brings more CFTR proteins to the cell surface

• Ivacaftor helps CFTR proteins stay open longer at the cell surface

CFTR Amplifiers

Increase the amount of CFTR protein that each cell makes; would be helpful for people with CF who don’t make enough CFTR protein.

• Not on the market yet

• Nesolicaftor is in clinical trial

Airway Clearance

• Recombinant human DNase I, an enzyme with a primary amino acid sequence that is identical to the native human enzyme

  • Biosynthetic form of human DNase I, produced in the genetically modified Chinese hamster ovary

• Mucolytic agent (i.e., breaks up mucus)

• Targets and cleaves extracellular DNA to decrease mucus viscosity