Novel targeting strategy based on multimeric ligands for drug delivery and molecular imaging: Homooligomers of α-MSH

Josef Vagner; Heather L. Handl; Robert J. Gillies; Victor J. Hruby

doi:10.1016/j.bmcl.2003.09.079

Novel targeting strategy based on multimeric ligands for drug delivery and molecular imaging: Homooligomers of α-MSH

Josef Vagner, Heather L. Handl, Robert J. Gillies, Victor J. Hruby

Research output: Contribution to journal › Article › peer-review

57 Scopus citations

Abstract

Homooligomers constructed with 4- and 6-amino acid fragments of melanocortin (α-MSH) bind with higher affinity and with apparent cooperativity to melanocortin receptor, compared to their constituent monomers. Individual ligands were tethered with various spacers of different length and rigidity and the influence of spacers on binding was studied. Binding assays were performed on cells transfected with the melanocortin receptor, hMC4R. There is a 5-7-fold decrease in the EC₅₀ with the addition of each subunit, going from monomer to trimer. The Hill coefficient increases from 0.76 for the monomer to 1.12 for the dimer and 1.35 for the trimer. These data show a general trend of increasing avidity with increasing number of ligands in oligomers.

Original language	English (US)
Pages (from-to)	211-215
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	14
Issue number	1
DOIs	https://doi.org/10.1016/j.bmcl.2003.09.079
State	Published - Jan 5 2004

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2003.09.079

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title = "Novel targeting strategy based on multimeric ligands for drug delivery and molecular imaging: Homooligomers of α-MSH",

abstract = "Homooligomers constructed with 4- and 6-amino acid fragments of melanocortin (α-MSH) bind with higher affinity and with apparent cooperativity to melanocortin receptor, compared to their constituent monomers. Individual ligands were tethered with various spacers of different length and rigidity and the influence of spacers on binding was studied. Binding assays were performed on cells transfected with the melanocortin receptor, hMC4R. There is a 5-7-fold decrease in the EC50 with the addition of each subunit, going from monomer to trimer. The Hill coefficient increases from 0.76 for the monomer to 1.12 for the dimer and 1.35 for the trimer. These data show a general trend of increasing avidity with increasing number of ligands in oligomers.",

author = "Josef Vagner and Handl, {Heather L.} and Gillies, {Robert J.} and Hruby, {Victor J.}",

note = "Funding Information: This research was supported by NIH grant R21 CA95944 (R.J.G.) and DK 17420 (V.J.H.). Special thanks to MinYing Cai for help with binding assays.",

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AU - Handl, Heather L.

AU - Gillies, Robert J.

AU - Hruby, Victor J.

N1 - Funding Information: This research was supported by NIH grant R21 CA95944 (R.J.G.) and DK 17420 (V.J.H.). Special thanks to MinYing Cai for help with binding assays.

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N2 - Homooligomers constructed with 4- and 6-amino acid fragments of melanocortin (α-MSH) bind with higher affinity and with apparent cooperativity to melanocortin receptor, compared to their constituent monomers. Individual ligands were tethered with various spacers of different length and rigidity and the influence of spacers on binding was studied. Binding assays were performed on cells transfected with the melanocortin receptor, hMC4R. There is a 5-7-fold decrease in the EC50 with the addition of each subunit, going from monomer to trimer. The Hill coefficient increases from 0.76 for the monomer to 1.12 for the dimer and 1.35 for the trimer. These data show a general trend of increasing avidity with increasing number of ligands in oligomers.

AB - Homooligomers constructed with 4- and 6-amino acid fragments of melanocortin (α-MSH) bind with higher affinity and with apparent cooperativity to melanocortin receptor, compared to their constituent monomers. Individual ligands were tethered with various spacers of different length and rigidity and the influence of spacers on binding was studied. Binding assays were performed on cells transfected with the melanocortin receptor, hMC4R. There is a 5-7-fold decrease in the EC50 with the addition of each subunit, going from monomer to trimer. The Hill coefficient increases from 0.76 for the monomer to 1.12 for the dimer and 1.35 for the trimer. These data show a general trend of increasing avidity with increasing number of ligands in oligomers.

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Novel targeting strategy based on multimeric ligands for drug delivery and molecular imaging: Homooligomers of α-MSH

Abstract

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