L10 Advances in drugs targeting the parathyroid glands Flashcards
Role of PTH
Maintenance of adequate levels of blood ionized calcium (free calcium)
- normal neuromuscular function
- bone mineralisation
What cells in the parathyroid gland secrete PTH, and in response to what?
Chief cells secrete PTH in response to small decreases in blood ionized calcium in order to maintain calcium homeostasis
Effect of PTH secretion on calcium
- increased intestinal absorption of calcium
- increased renal calcium reabsorption
- increased bone resorption, which increases calcium since bone is a calcium store
How is PTH synthesised?
PTH is synthesised as a prepropeptide hormone comprising 115 amino acids, but only the single chain full length polypeptide is secreted. The preprohormone and prohormone have little/no biological effect and are not released.
Factors influencing PTH synthesis
- cAMP acting via cAMP response element binding protein upregulates PTH gene transcription
- vitamin D downregulates PTH transcription
- low serum calcium levels upregulate PTH synthesis
- high serum phosphate levels upregulate PTH synthesis
PTH is a product of a single gene located on which chromosome?
11
Why is the structure of PTH important?
As many as 50 amino acids can be removed from the C-terminus without compromising biological potency. However, removal of serine at the N-terminus virtually inactivates the hormone.
How many amino acids does PTH contain?
84
Where is parathyroid hormone-related peptide (PTHrP) found?
in the plasma of patients suffering from certain malignancies and accounts for the accompanying hypercalcaemia (little/no PTHrP found in normal individuals)
What allows PTHrP to bind PTH1R with high affinity?
- similar first 13 amino acids to PTH
- similarities in the N-terminus to PTH
What type of receptor is PTH receptor?
G-protein coupled receptor
Which enzymes are important in regulation of calcium levels and are a result of Gαs and Gαq stimulation, respectively?
PKA and PKC
Rapid response to PTH
protein phosphorylation
Delayed response to PTH
altered expression of genes regulated by cAMP response element binding protein
Increased PTH causes bone resorption, so how can PTH help with osteoporosis?
Intermittent PTH administration has anabolic effects. This results in bone formation and increased osteoblast number, which is beneficial in osteoporosis treatment.
How are intermittent PTH levels achieved?
When dosed daily because PTH is cleared within 2-3 hours of administration - intermittent increase in PTH
What does continuous administration of PTH or high circulating PTH levels (e.g. in primary hyperparathyroidism) cause?
bone demineralisation and osteopenia
Examples of human recombinant PTH (rhPTH)?
- Teriparatide (PTH 1-34) - osteoporosis treatment
- Full length recombinant PTH (1-84): Preotact (awaiting approval) and Natpar (hypoparathyroidism)
- Ostabolin (cyclic PTH 1-35) - in development
Example of a PTHrP synthetic analog and its clinical indication
Abaloparatide (Tymlos) - approved in 2017 for the treatment of osteoporosis
How does Abaloparatide work?
Binds to RG conformation of PTH1R with greater selectivity and activates both cAMP and β-arrestin pathways with similar potency
What is characteristic of hypoparathyroidism?
- decreased PTH release
- lack of control over serum calcium levels
- chronic hypocalcaemia
3 types of hypoparathyroidism
- Genetically-induced abnormal gland formation, impaired PTH production or altered PTH secretion
- Decreased parathyroid gland function due to surgery, autoimmune diseases or infiltrative conditions
- Resistance to PTH: pseudohypoparathyroidism
Two examples of PTH analogs (not approved)
- AZP-3601 (increased Ca levels & deemed safe in clinical trials)
- LY627-2K (promising results regarding serum Ca levels) - repurposed for hypoparathyroidism (tolerability issues arose when trialled for osteoporosis)
Example of a prodrug of PTH
Transcon-PTH
How does Transcon-PTH work?
Parent drug + Transcon carrier + Transcon linker
Linker cleavage dependent upon pH & temp. When linker dissolves, active PTH is released. The linker prolongs PTH release and inhibits its binding until release.
Why are subcutaneous preparations of PTH analogs devised to prolong the half-life of the molecules?
to increase their biological activity
Hyperparathyroidism is characterised by…
hypercalcaemia and elevated PTH levels
Main cause of hyperparathyroidism
benign overgrowth of parathyroid tissue (mainly adenoma) causing excess secretion of PTH
What is secondary hyperparathyroidism?
Parathyroid glands become enlarged and hyperactive in response to a condition outside of the parathyroid gland (most commonly CKD)
Current treatment for hyperparathyroidism
Surgical removal of the parathyroid gland (currently no pharmacological treatments)
What effect does Sema3d have in hyperparathyroidism?
Sema3d inhibits parathyroid proliferation via inhibition of the EGFR/ErbB signalling pathway. Sema3d knockout mice develop hyperparathyroidism.
