Rigid linkers for bioactive peptides.
Rigid linkers of variable length were used to connect two high-affinity Nle4-D-Phe7-alpha-melanocyte stimulating hormone (NDP-alpha-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-alpha-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.
Vagner
Josef
J
Department of Chemistry, University of Arizona, Tucson, Arizona 85721, USA.
Handl
Heather L
HL
Monguchi
Yasunari
Y
Jana
Umasish
U
Begay
Lucinda J
LJ
Mash
Eugene A
EA
Hruby
Victor J
VJ
Gillies
Robert J
RJ
D002460:Cell Line; D003432:Cross-Linking Reagents / Q000737:chemistry*; D019281:Dimerization; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D044105:Receptor, Melanocortin, Type 4 / Q000378:metabolism
D003432:Cross-Linking Reagents; D008024:Ligands; D010455:Peptides; D044105:Receptor, Melanocortin, Type 4