The development of functionalised stapled peptides as chemical tools to modulate biological processes in platelets and as novel antimicrobial therapeutics targeting Pseudomonas aeruginosa
Peptides are useful modulators of protein-protein interactions (PPIs) and cellular membranes, both of which are traditionally challenging to target using small molecules. Often therapeutic peptides suffer from issues including poor proteolytic stability. Two-component peptide stapling can improve stability and enable facile peptide functionalisation. This thesis describes the development of functionalised stapled peptides for two biological applications.
- The development of stapled peptides as chemical tools to investigate PPIs in human platelets Platelets are a vital, anuclear component of blood. The Bcl-2 family of proteins are known to be key mediators of apoptosis in nucleated cells, however the role of each Bcl-2 protein in platelet apoptosis and activation is unknown. Recently, stapled peptides were deemed useful chemical tools for studying PPIs in platelets. In this section, three polyarginine-functionalised stapled peptides were developed as Bcl-2 PPI inhibitors. These novel chemical tools are anticipated to provide valuable insight into the roles of Bcl-2 PPIs in platelet modulation, which could ultimately lead to new therapeutic targets.
- The development of cleavable stapled peptide-drug conjugates to target Pseudomonas aeruginosa Antimicrobial resistance (AMR) is a major healthcare threat, and Gram-negative bacteria such as Pseudomonas aeruginosa pose a significant therapeutic challenge. Antimicrobial peptides disrupt bacterial membranes, however functionalised two-component stapled antimicrobial peptides (STAMPs) are underexplored. This section describes the development of a STAMP-drug conjugate, constructed by functionalisation of the STAMP staple with a small molecule antibiotic, attached via a β-lactamase-cleavable motif. The resulting conjugate combines two mechanisms of action, which is a validated strategy for overcoming AMR. To this end, two novel, unfunctionalised STAMPs were identified that exhibited good minimum inhibitory concentrations against P. aeruginosa (64 μg/mL) and selectivity over a Gram-positive strain, from a panel of seven novel STAMPs. Subsequently, a tractable synthesis of the proposed functionalised STAMP was investigated. It is hypothesised that the cleavable STAMP-drug conjugate will enable infection-controlled drug-release and dual-targeting of P. aeruginosa.