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November 8, 2018
11 am to 12 pm EST
 
Polar Hinges as Functionalized Conformational Constraints in (Bi)cyclic Peptides  

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Webinar Description:
Protein-protein interactions (PPI’s) mediate interactions that are not only essential to homeostasis, but are also responsible for initiating and maintaining a range of physiological disorders. As a result, the inhibition of PPI's is of increasing importance to the field of drug discovery. Despite the progress that has been made in the field of PPI modulation, the development of molecules that can interfere with protein-protein interactions remains challenging. Since contact surfaces involved in PPI’s are normally large and flat, it is a serious challenge for the traditional “small-molecule” approach to effectively disrupt such a large interface. In order to address this issue, we wish to devise larger biomolecular constructs, such as cyclic peptides and peptidomimetics as PPI inhibitors. The Liskamp group has developed 'Polar hinges’ (see 'Polar Hinges as Functionalized Conformational Constraints in (Bi)cyclic Peptides, ChemBioChem, 2017, 18 (4), 387-395') as scaffolds for the cyclization of peptides, which in turn yielded bicyclic peptides and cyclized peptides with improved solubility and biological activity. During the course of this research, we noted that aqueous solubility of candidate PPI inhibitors is an absolute prerequisite not only to be able to handle and purify our target peptides; but this intrinsic property is also crucial for validation of biological activity.”

Learning Objectives:

  • Challenges in the development of molecules that interfere with protein-protein interactions (PPI inhibitors)
  • Cyclic peptides and peptidomimetics as PPI inhibitors
  • Polar hinges as scaffolds for the cyclization of peptides to yield bicyclic peptides and cyclized peptides
  • Importance of aqueous solubility of candidate PPI inhibitors in the validation of biological activity

Speakers:

Alex Hoose image

Dr Alex Hoose
Post-Doctoral Research Associate
University of Glasgow

Alex Hoose obtained his Master’s degree in Chemistry from the University of Durham, UK (2010). He subsequently worked in peptide production at Cambridge Research Biochemicals, prior to undertaking pharmaceutical research at Medimmune into the development of peptides for the treatment of neuropathic pain and diabetes. He subsequently obtained his PhD in Biochemistry from the University of Southampton, UK (2016) where he conducted research into cap-dependent translation inhibitors in collaboration with Dr. Mark Coldwell. Alex then conducted post-Doctoral research (2016-2017) focused on the development of peptide metalloprotease inhibitors under the supervision of Dr. Andrew Jamieson. He is currently a post-Doctoral Research associate (2017-present) in the group of Prof. Rob Liskamp within the School of Chemistry at the University of Glasgow, UK. His research interests include the application of peptides as pesticides, pharmaceuticals and tools for the development of antibody-drug conjugates.

Rob Liskamp image

Professor Rob Liskamp
Chair of Chemical Biology and Medicinal Chemistry & Guest Professor of Molecular Medicinal Chemistry at Utrecht University
University of Glasgow & Utrecht University (The Netherlands)

Rob Liskamp obtained his Ph.D. Bio-organic Chemistry at the University of Nijmegen, The Netherlands (1982). Post-doctoral research (1983-1986) was carried out in The Institute of Cancer Research and Department of Chemistry of Columbia University, New York. From 1986-1993 he was an assistant professor at the University of Leiden. In 1991 he was a visiting professor at the University of California in Los Angeles. In 1994 he became associate professor at Utrecht University and in 1996 professor of Molecular Medicinal Chemistry. In 2012, he was a visiting professor at the Universities of Leeds and Glasgow. In 2013 he was appointed Professor and Chair of Chemical Biology and Medicinal Chemistry at the University of Glasgow, while maintaining a guest appointment as professor at the University of Utrecht. Research interests include (enzymatic) synthesis of biologically active modified peptides and peptidomimetics, dendrimers, peptide folding, protein mimics including synthetic antibodies and vaccines.

 

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