Poster Presentation 12th Australian Peptide Conference 2017

Multivalent Ligand Design – Chemistry and Applications (#175)

Markus Muttenthaler 1 2 3 , Marta Busnelli 4 , Gunnar Kleinau 5 , Maurice Manning 6 , Bice Chini 4 , Paul F Alewood 1 , Joyce C Berger 7 , James B Delehanty 7 , Darren A Thompson 8 , Philip E Dawson 3 , Igor L Medintz 7
  1. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld, Australia
  2. Institute of Biological Chemistry, University of Vienna, Vienna, Austria
  3. The Scripps Research Institute, La Jolla, CA, USA
  4. CNR, Institute of Neuroscience, Milan, Italy
  5. Institute of Experimental Pediatric Endocrinology, Charite-Universitaetsmedizin Berlin, Berlin, Germany
  6. Department of Biochemistry and Cancer Biology, University of Toledo, Toledo, Ohio, USA
  7. Center for Bio/Molecular Science and Engineering, US Naval Research Laboratory, Washington, DC, USA
  8. University of Idaho, Coeur d’Alene, ID, USA

Multivalent interactions are widely observed in nature yet relatively underexplored in ligand design and drug development. Dendritic structures of neurons, vasculature, viral surface proteins, roots and river deltas are just a few examples where biological function is transferred in a branched fashion. Chemically, multivalent interactions and dendritic structures have been explored in biomaterials, catalysis, gene delivery and vaccine development, however, the therapeutic prospect of multivalent ligands has yet to be established. Our lab is interested in chemical strategies to efficiently assemble a diverse range of monodisperse, well-defined, multifunctional peptide dendrimers, so we can explore their potential as a novel class of molecular probes, drug leads and theranostics.

 

Here we present our synthetic strategies to produce different sets of multivalent (2x, 4x, 8x, 16x) peptide ligands. Design rationale, the different chemistries employed, pharmacological and biophysical characterisation, and the synthetic challenges that were faced will be discussed. Biological applications of these multivalent ligands include G protein-coupled receptor interaction which resulted in substantial potency improvements, and the use of poly-arginine peptide dendrimers to improve intracellular delivery of nanoparticles decorated with drug cargo. The chemical strategies employed in this work are broadly applicable for the synthesis of other complex peptide constructs, and our biological results strongly highlight the versatility of multivalent ligands as molecular probes and potential drug leads.