Solid-phase peptide head-to-side chain cyclodimerization: discovery of C(2)-symmetric cyclic lactam hybrid α-melanocyte-stimulating hormone (MSH)/agouti-signaling protein (ASIP) analogues with potent activities at the human melanocortin receptors.
A novel hybrid melanocortin pharmacophore was designed based on the pharmacophores of the agouti-signaling protein (ASIP), an endogenous melanocortin antagonist, and α-melanocyte-stimulating hormone (α-MSH), an endogenous melanocortin agonist. The designed hybrid ASIP/MSH pharmacophore was explored in monomeric cyclic, and cyclodimeric templates. The monomeric cyclic disulfide series yielded peptides with hMC3R-selective non-competitive binding affinities. The direct on-resin peptide lactam cyclodimerization yielded nanomolar range (25-120 nM) hMC1R-selective full and partial agonists in the cyclodimeric lactam series which demonstrates an improvement over the previous attempts at hybridization of MSH and agouti protein sequences. The secondary structure-oriented pharmacophore hybridization strategy will prove useful in development of unique allosteric and orthosteric melanocortin receptor modulators. This report also illustrates the utility of peptide cyclodimerization for the development of novel GPCR peptide ligands.
Mayorov
Alexander V
AV
Department of Chemistry and Biochemistry, University of Arizona, 1306 E. University Blvd., Tucson, AZ 85721, USA.
Cai
Minying
M
Palmer
Erin S
ES
Liu
Zhihua
Z
Cain
James P
JP
Vagner
Josef
J
Trivedi
Dev
D
Hruby
Victor J
VJ
D054366:Agouti Signaling Protein / Q000138:chemical synthesis / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000242:Cyclic AMP / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D044101:Receptors, Melanocortin / Q000378:metabolism*; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism
D054366:Agouti Signaling Protein; D007769:Lactams; D010456:Peptides, Cyclic; D044101:Receptors, Melanocortin; D000521:alpha-MSH; D000242:Cyclic AMP