AbstractCystic fibrosis (CF) is an autosomal recessive disease affecting over 100,000 patients globally. Current treatments are limited due to several types of mutations affecting the CFTR gene and are costly to healthcare providers. Therefore, new treatment options are required. Studies at Queens University Belfast have shown that Cathepsin S (CatS), a cysteine protease, is elevated in 100% of CF patients. Further studies have shown that CatS is involved in structural damage of the lung tissue, antiproteases degradation, mucus production, and antimicrobial peptides degradation. Moreover, CatS knockout has been shown to improve bacterial clearance and to reduce inflammation. To effectively treat CF patients, we are aiming to synthesize an inhaled CatS inhibitor. Inhaled drugs are more efficient in treating respiratory diseases due to the delivery of higher concentrations locally than systemically administered compounds. Therefore, there are certain essential physical and chemical properties that are required to achieve an effective inhaled drug such as, high potency and selectivity, low systemic exposure, and long duration of action.
In chapter 1, we attempted to synthesize cyanopyrimidine CatS inhibitors based on the work of Irie and colleagues. They were able to produce a few potent CatS inhibitors by switching the selectivity of a CatK inhibitor. In addition, the selectivity of those inhibitors against CatK, and L can be massively improved. Therefore, a series of SAR (Structure-activity relationship) optimization was carried out to improve the potency and the selectivity of the scaffold however, the results did not meet our potency criteria. The work of chapter 2 was based on previous (unpublished data) in our lab, which resulted in developing very potent CatS inhibitors with excellent potency and cellular activity, but poor solubility. Therefore, optimization of the inhibitors to improve the Solubility was needed. The optimization was achieved via a series of SAR studies of the P3 and P2 moieties of the inhibitors. Although our findings revealed high potency and selectivity, further optimization is required to improve the cellular activity of the inhibitors.
Thesis is embargoed until 31 December 2027.
|Date of Award||Dec 2022|
|Sponsors||Marie Sklodowska Curie COFUND|
|Supervisor||Richard Williams (Supervisor) & Christopher Scott (Supervisor)|
- cathepsin S
- Protease inhibitors
- small molecules
- Drug discovery
- cystic fibrosis
- inhaled delivery
- inhaled drugs