Please join us for the March edition of the PPSG Early Career Academic seminar series. This month's speakers will be Scott Lovell from the University of Bath and Clarissa Czekster from University of St. Andrews.
On line Zoom lecture
Scott Lovell – University of Bath
Title: Screening Approaches for the Identification of Covalent Peptide Inhibitors
Abstract: Stratified medicine is poised to fundamentally alter cancer therapy but is currently limited to just 10% of patients. This is due to a lack of inhibitors for most cancer proteins, which are often deemed undruggable as they lack binding pockets that can be targeted with small molecules.
Undruggable proteins possess reactive nucleophilic residues that can be interrogated by targeted covalent inhibitors (TCIs). Most TCIs target cysteines, but many proteins lack cysteine residues. Electrophiles have been reported for nine other amino acids, but few unbiased screening methods exist to identify TCIs from diverse pools of candidate molecules. Consequently, the full potential of TCIs for targeting undruggable proteins is yet to be realised.
Our research aims to address this by using combinatorial chemistry and phage display to develop ultra-large libraries of covalent peptides for screening. Specifically, we develop libraries of targeted covalent cyclic peptides (TCCPs) by cyclising billions of phage-displayed linear peptides with reactive linkers possessing latent electrophilic moieties. TCCPs have the combined properties of a macrocyclic peptide (high affinity and specificity) and a covalent inhibitor (durable target engagement) and are particularly effective at engaging undruggable protein targets.
Clarissa Czekster – University of St Andrews
Title: Designing antibiofilm cyclic peptides targeting extracellular proteases
Abstract: Bacteria frequently grow in complex communities called biofilms, which are resilient to stress, nutrient shortages and antibiotic treatment. No drug in the market specifically targets bacterial biofilms. In this presentation I will discuss targeting extracellular bacterial virulence factors as a strategy to specifically modulate bacterial biofilms. Extracellular proteases and peptidases are crucial to nutrient scavenging, biofilm remodelling and degradation of toxic proteins and peptides. By understanding the mechanism by which peptidases switch from inactive to active states we can design cyclic peptide mimics to trap proteins in a self-inhibited state
If you would like to present in future seminars, please contact one of the organisers. We welcome presentations from early career UK-based academics or senior postdoctoral researchers seeking to establish an independent career in peptide and protein science.
Louis Luk: lukly@cardiff.ac.uk
Chris Coxon: chris.coxon@ed.ac.uk
Louise Walport: louise.walport@crick.ac.uk
On line Zoom lecture
Scott Lovell – University of Bath
Title: Screening Approaches for the Identification of Covalent Peptide Inhibitors
Abstract: Stratified medicine is poised to fundamentally alter cancer therapy but is currently limited to just 10% of patients. This is due to a lack of inhibitors for most cancer proteins, which are often deemed undruggable as they lack binding pockets that can be targeted with small molecules.
Undruggable proteins possess reactive nucleophilic residues that can be interrogated by targeted covalent inhibitors (TCIs). Most TCIs target cysteines, but many proteins lack cysteine residues. Electrophiles have been reported for nine other amino acids, but few unbiased screening methods exist to identify TCIs from diverse pools of candidate molecules. Consequently, the full potential of TCIs for targeting undruggable proteins is yet to be realised.
Our research aims to address this by using combinatorial chemistry and phage display to develop ultra-large libraries of covalent peptides for screening. Specifically, we develop libraries of targeted covalent cyclic peptides (TCCPs) by cyclising billions of phage-displayed linear peptides with reactive linkers possessing latent electrophilic moieties. TCCPs have the combined properties of a macrocyclic peptide (high affinity and specificity) and a covalent inhibitor (durable target engagement) and are particularly effective at engaging undruggable protein targets.
Clarissa Czekster – University of St Andrews
Title: Designing antibiofilm cyclic peptides targeting extracellular proteases
Abstract: Bacteria frequently grow in complex communities called biofilms, which are resilient to stress, nutrient shortages and antibiotic treatment. No drug in the market specifically targets bacterial biofilms. In this presentation I will discuss targeting extracellular bacterial virulence factors as a strategy to specifically modulate bacterial biofilms. Extracellular proteases and peptidases are crucial to nutrient scavenging, biofilm remodelling and degradation of toxic proteins and peptides. By understanding the mechanism by which peptidases switch from inactive to active states we can design cyclic peptide mimics to trap proteins in a self-inhibited state
If you would like to present in future seminars, please contact one of the organisers. We welcome presentations from early career UK-based academics or senior postdoctoral researchers seeking to establish an independent career in peptide and protein science.
Louis Luk: lukly@cardiff.ac.uk
Chris Coxon: chris.coxon@ed.ac.uk
Louise Walport: louise.walport@crick.ac.uk
