Rigid linkers for bioactive peptides

Josef Vagner, Heather L. Handl, Yasunari Monguchi, Umasish Jana, Lucinda J. Begay, Eugene A. Mash, Victor J. Hruby, Robert J. Gillies

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Rigid linkers of variable length were used to connect two high-affinity Nle4-D-Phe7-α-melanocyte stimulating hormone (NDP-α-MSH) or two low-affinity MSH(4) ligands. The linked peptides were synthesized by solid-phase methods. Control experiments indicate there is little or no effect of these linkers on NDP-α-MSH or MSH-(4) binding to the human melanocortin 4 receptor (hMC4R). Tethering two high-affinity ligands gave no binding enhancement, while tethering two low-affinity ligands resulted in binding enhancement that decreased with increased linker length. Furthermore, for the low-affinity ligands, the enhancement of affinity is inversely proportional to the estimated molecular moments of inertia. These results are consistent with a model wherein binding is enhanced when the rate of ligand reattachment to the receptor is fast relative to the rate of ligand diffusion.

Original languageEnglish (US)
Pages (from-to)1545-1550
Number of pages6
JournalBioconjugate Chemistry
Volume17
Issue number6
DOIs
StatePublished - Nov 1 2006

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

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    Vagner, J., Handl, H. L., Monguchi, Y., Jana, U., Begay, L. J., Mash, E. A., Hruby, V. J., & Gillies, R. J. (2006). Rigid linkers for bioactive peptides. Bioconjugate Chemistry, 17(6), 1545-1550. https://doi.org/10.1021/bc060154p