Oral Presentation 5th Modern Solid Phase Peptide Synthesis Symposium 2015

Synthesis of [lys8]-oxytocin dendrimers that maintain potency and structure and inhibit visceral nociceptive responses (#2)

Jingjing Wan 1 , Mehdi Mobli 2 , Andreas Brust 1 , Markus Muttenthaler 1 , Åsa Andersson 1 , Lotten Ragnarsson 1 , Joel Castro 3 , Irina Vetter 1 , Johnny Huang 1 , Mathias Nilsson 4 , Stuart M. Brierley 3 , Matthew A. Cooper 1 , Richard J. Lewis 1 , Paul Alewood 1
  1. Institute of Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
  2. Centre for Advanced Imaging, The University of Queensland, St Lucia, QLD, Australia
  3. The University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia
  4. School of Chemistry, University of Manchester, Manchester, UK

Bioactive peptide dendrimers comprise a new class of precisely defined macromolecules that in principle may demonstrate enhanced pharmaceutical properties via enabling polyvalent interaction between multiple receptors, enhanced resistance to proteolysis and delayed renal clearance due to their higher molecular weights. Here, we describe the solid phase synthesis, structure, binding affinity, selectivity, functional activity and anti-nociceptive properties of [lys8]-oxytocin (LVT) dendrimers containing up to 16 copies of LVT. These were generated using a CuAAc reaction with azido-pegylated LVT peptides on an alkyne-polylysine scaffold. 2D NMR analysis demonstrated that each attached LVT ligand was freely rotating and maintained identical 3D structures in each dendrimeric macromolecule. The binding affinity of the LVT dendrimers increased with low generation dendrimers and decreased in higher generations without affecting selectivity with increases ~17-, ~12-, ~3- and ~1.5- fold respectively for the 2-, 4-, 8- and 16-mer dendrimeric LVT conjugates suggesting a multivalent interaction. A similar trend in affinity was also observed at the related human V1a, V1b and V2 receptors, with no significant selectivity change observed across this family of receptors. All LVT dendrimers were functionally active in vitro on human OT receptors and potently inhibited colonic nociceptors in a mouse model of chronic abdominal pain.