Conformationally Constrained Macrocycles and their Applications
Lead Research Organisation:
University of Cambridge
Department Name: Chemistry
Abstract
Inhibition of protein-protein interactions (PPIs) represents a significant challenge when applying traditional small molecule drug discovery methods. Stapled peptides are rationally-designed inhibitors of PPIs, in which amino acid side chains are covalently linked to reinforce the optimal conformation for binding a target protein. PPIs play a central role in all biological processes and represent an important target space for pharmacological intervention. Abnormal PPIs can disrupt critical cellular processes and lead to human diseases. Thus, the ability to control and modulate these PPIs could potentially open up a vast array of new molecular therapeutics. However, inhibition of PPIs has proved to be a significant challenge when applying traditional small molecule drug discovery methods, due to the large surface area of PPI interfaces, as well as the lack of natural small molecule binder from which to design inhibitors. In contrast, peptides are well suited to bind proteins at PPI interfaces. Unfortunately peptides make poor therapeutic candidates due to their lack of cell permeability and susceptibility to proteolysis. A promising method for circumventing these issues is peptide stapling: the covalent linking of side-chains to lock a peptide into a particular conformation. This research aims to develop novel macrocycles of peptides and peptidomimetics and to apply them in various applications.
Organisations
Publications
Charoenpattarapreeda J
(2019)
Targeted covalent inhibitors of MDM2 using electrophile-bearing stapled peptides.
Charoenpattarapreeda J
(2019)
Targeted covalent inhibitors of MDM2 using electrophile-bearing stapled peptides.
in Chemical communications (Cambridge, England)
Robertson NS
(2019)
Macrocyclisation and functionalisation of unprotected peptides via divinyltriazine cysteine stapling.
in Chemical communications (Cambridge, England)
Sharma K
(2020)
Functionalized Double Strain-Promoted Stapled Peptides for Inhibiting the p53-MDM2 Interaction.
in ACS omega
Sharma K
(2019)
Water-soluble, stable and azide-reactive strained dialkynes for biocompatible double strain-promoted click chemistry.
in Organic & biomolecular chemistry
Wu Y
(2019)
Toolbox of Diverse Linkers for Navigating the Cellular Efficacy Landscape of Stapled Peptides.
in ACS chemical biology
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
EP/N509620/1 | 30/09/2016 | 29/09/2022 | |||
1800602 | Studentship | EP/N509620/1 | 30/09/2016 | 29/09/2020 | Elaine Fowler |