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SUMMARY:Screening Approaches for the Identification of Covalent Peptide In
 hibitors - Scott Lovell\, University of Bath
DTSTART:20240318T123000Z
DTEND:20240318T133000Z
UID:TALK213160@talks.cam.ac.uk
CONTACT:Kate Davenport
DESCRIPTION: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 dee
 med undruggable as they lack binding pockets that can be targeted with sma
 ll 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. Electrophile
 s have been reported for nine other amino acids\, but few unbiased screeni
 ng methods exist to identify TCIs from diverse pools of candidate molecule
 s. Consequently\, the full potential of TCIs for targeting undruggable pro
 teins is yet to be realised. \nOur 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 o
 f targeted covalent macrocycles (TCMs) by cyclising billions of phage-disp
 layed linear peptides with reactive linkers possessing latent electrophili
 c moieties. TCMs have the combined properties of a macrocyclic peptide (hi
 gh affinity and specificity) and a covalent inhibitor (durable target enga
 gement) and are particularly effective at engaging undruggable protein tar
 gets.\n1.            Chen\, S.\, Lovell\, S.\, Lee\, S.\, Fellner\, M.\, M
 ace\, P. D.\, & Bogyo\, M. (2021). Identification of highly selective cova
 lent inhibitors by phage display. Nature Biotechnology\, 39 (4)\, 490–49
 8.\n2.            Lovell\, S.\, et al.\, (2021). A Suite of Activity-Based
  Probes To Dissect the KLK Activome in Drug-Resistant Prostate Cancer. Jou
 rnal of the American Chemical Society\, 143 (23)\, 8911–8924.\n
LOCATION:CRUK CI Lecture Theatre
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