Synthesis, biophysical, and pharmacological evaluation of the melanocortin agonist AST3-88: modifications of peptide backbone at Trp 7 position lead to a potent, selective, and stable ligand of the melanocortin 4 receptor (MC4R).
Synthesis, biophysical, and pharmacological evaluation of the melanocortin agonist AST3-88: modifications of peptide backbone at Trp 7 position lead to a potent, selective, and stable ligand of the melanocortin 4 receptor (MC4R).
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黑皮质素激动剂 AST3-88 的合成、生物物理和药理学评估：Trp 7 位点肽主链的修饰产生了黑皮质素 4 受体 (MC4R) 的有效、选择性和稳定的配体。
DOI：
10.1021/cn5000953
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发表时间：
2014-10-15
影响因子：
5
通讯作者：
Haskell-Luevano, Carrie
中科院分区：
文献类型：
--
作者：
Singh, Anamika;Dirain, Marvin L.;Wilczynski, Andrzej;Chen, Chi;Gosnell, Blake A.;Levine, Allen S.;Edison, Arthur S.;Haskell-Luevano, Carrie
关键词：
The melanocortin-3 (MC3R) and melanocortin-4 (MC4R) receptors are expressed in the brain and are implicated in the regulation of food intake and energy homeostasis. The endogenous agonist ligands for these receptors (α-, β-, γ-MSH and ACTH) are linear peptides with limited receptor subtype selectivity and metabolic stability, thus minimizing their use as probes to characterize the overlapping pharmacological and physiological functions of the melanocortin receptor subtypes. In the present study, an engineered template, in which the peptide backbone was modified by a heterocyclic reverse turn mimetic at the Trp7 residue, was synthesized using solid phase peptide synthesis and characterized by a β-galactosidase cAMP based reporter gene assay. The functional assay identified a ∼5 nM mouse MC4R agonist (AST3-88) with more than 50-fold selectivity over the mMC3R. Biophysical studies (2D 1H NMR spectroscopy and molecular dynamics) of AST3-88 identified a type VIII β-turn secondary structure spanning the pharmacophore domain stabilized by the intramolecular interactions between the side chains of the His and Trp residues. Enzymatic studies of AST3-88 revealed enhanced stability of AST3-88 over the α-MSH endogenous peptide in rat serum. Upon central administration of AST3-88 into rats, a decreased food intake response was observed. This is the first study to probe the in vivo physiological activity of this engineered peptide-heterocycle template. These findings advance the present knowledge of pharmacophore design for potent, selective, and metabolically stable melanocortin ligands.
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影响因子：
7.3
作者：
HASKELLLUEVANO, C;BOTEJU, LW;HRUBY, VJ
通讯作者：
HRUBY, VJ
影响因子：
2.9
作者：
CHEN, WB;SHIELDS, TS;CONE, RD
通讯作者：
CONE, RD
DOI：
10.1006/bbrc.1993.2125
发表时间：
1993-09-15
影响因子：
3.1
作者：
CHHAJLANI, V;MUCENIECE, R;WIKBERG, JES
通讯作者：
WIKBERG, JES
影响因子：
7.3
作者：
Holder, JR;Xiang, ZM;Haskell-Leuvano, C
通讯作者：
Haskell-Leuvano, C
DOI：
10.1111/j.1749-6632.2003.tb03160.x
发表时间：
2003-01-01
期刊：
MELANOCORTIN SYSTEM
影响因子：
--
作者：
Holder, JR;Haskell-Luevano, C
通讯作者：
Haskell-Luevano, C