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Carrie Haskellluevano - One of the best experts on this subject based on the ideXlab platform.
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peptoid nphe4 in agrp based c pro1 arg2 phe3 phe4 xxx5 ala6 phe7 dpro8 scaffolds maintain mouse mc4r antagonist potency
ACS Medicinal Chemistry Letters, 2020Co-Authors: Mark D Ericson, Katie T Freeman, Carrie HaskellluevanoAbstract:The melanocortin receptors are involved in numerous physiological functions and are regulated by agonists derived from the proopiomelanocortin gene transcript and two endogenous antagonists, agouti and agouti-related protein (AGRP). The key binding and functional determinant of AGRP, an MC3R and MC4R antagonist, is an Arg-Phe-Phe tripeptide sequence located on an exposed hexapeptide (Arg-Phe-Phe-Asn-Ala-Phe) loop. It has previously been observed that cyclizing this sequence through a DPro-Pro motif (c[Pro1-Arg2-Phe3-Phe4-Asn5-Ala6-Phe7-DPro8]) resulted in a macrocyclic scaffold with MC4R antagonist activity, with increased MC4R potency when a diaminopropionic acid (Dap) residue is substituted at position 5. In this report, a series of 11 single-peptoid substitutions were performed in the AGRP-derived macrocycles. While most peptoid substitutions decreased MC4R antagonist potency, it was observed that NPhe4 (compounds 4 and 11) or NDab5 (diaminobutyric acid, compound 7) maintained MC4R antagonist potency. The NPhe4 substitutions also resulted in MC5R antagonist and inverse agonist activity equipotent to the parent scaffolds. These data may be used in the design of future MC4R and MC5R antagonist leads and probes that possess increased metabolic stability due to the presence of peptoid residues.
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arg phe phe d amino acid stereochemistry scan in the macrocyclic agouti related protein antagonist scaffold c pro arg phe phe xxx ala phe dpro results in unanticipated melanocortin 1 receptor agonist profiles
ACS Chemical Neuroscience, 2018Co-Authors: Mark D Ericson, Katie T Freeman, Katlyn A Fleming, Zoe M Koerperich, Carrie HaskellluevanoAbstract:The melanocortin-3 and melanocortin-4 receptors (MC3R and MC4R), endogenous agonists derived from the proopiomelanocortin gene transcript, and naturally occurring antagonists agouti and agouti-related protein (AGRP) have been linked to biological pathways associated with energy homeostasis. The active tripeptide sequence of AGRP, Arg111-Phe112-Phe113, is located on a hypothesized β-hairpin loop. Herein, stereochemical modifications of the Arg-Phe-Phe sequence were examined in the octapeptide AGRP-derived macrocyclic scaffold c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was Asn or diaminopropionic acid (Dap). Macrocyclic peptides were synthesized with one, two, or three residues of the Arg-Phe-Phe sequence substituted with the corresponding d-isomer(s), generating a 14 compound library. While l-to-d inversions of the Arg-Phe-Phe sequence in a 20-residue AGRP-derived ligand previously resulted in agonist activity at the MC1R, MC3R, MC4R, and MC5R, only the MC1R was consistently stimulated by the macrocyclic ligands in the present study, with varying ligand potencies and efficacies observed at the MC1R. A general trend of increased MC4R antagonist potency was observed for Dap-containing compounds, while MC5R inverse agonist activity was observed for select ligands. It was observed that stereochemical modification of the Arg-Phe-Phe active tripeptide sequence was insufficient to convert melanocortin antagonist into agonists. Overall, these observations are important in the design of melanocortin ligands possessing potent and selective agonist and antagonist activities.
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arg phe phe d amino acid stereochemistry scan in the macrocyclic agouti related protein antagonist scaffold c pro arg phe phe xxx ala phe dpro results in unanticipated melanocortin 1 receptor agonist profiles
ACS Chemical Neuroscience, 2018Co-Authors: Mark D Ericson, Katie T Freeman, Katlyn A Fleming, Zoe M Koerperich, Carrie HaskellluevanoAbstract:The melanocortin-3 and melanocortin-4 receptors (MC3R and MC4R), endogenous agonists derived from the proopiomelanocortin gene transcript, and naturally occurring antagonists agouti and agouti-related protein (AGRP) have been linked to biological pathways associated with energy homeostasis. The active tripeptide sequence of AGRP, Arg111-Phe112-Phe113, is located on a hypothesized β-hairpin loop. Herein, stereochemical modifications of the Arg-Phe-Phe sequence were examined in the octapeptide AGRP-derived macrocyclic scaffold c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was Asn or diaminopropionic acid (Dap). Macrocyclic peptides were synthesized with one, two, or three residues of the Arg-Phe-Phe sequence substituted with the corresponding d-isomer(s), generating a 14 compound library. While l-to-d inversions of the Arg-Phe-Phe sequence in a 20-residue AGRP-derived ligand previously resulted in agonist activity at the MC1R, MC3R, MC4R, and MC5R, only the MC1R was consistently stimulated by the macrocycl...
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structure activity relationship studies on a macrocyclic agouti related protein agrp scaffold reveal agouti signaling protein asp residue substitutions maintain melanocortin 4 receptor antagonist potency and result in inverse agonist pharmacology at
Journal of Medicinal Chemistry, 2017Co-Authors: Mark D Ericson, Katie T Freeman, Sathya M Schnell, Katlyn A Fleming, Carrie HaskellluevanoAbstract:The melanocortin system consists of five reported receptors, agonists from the proopiomelanocortin gene transcript, and two antagonists, agouti-signaling protein (ASP) and agouti-related protein (AGRP). For both ASP and AGRP, the hypothesized Arg-Phe-Phe pharmacophores are on exposed β-hairpin loops. In this study, the Asn and Ala positions of a reported AGRP macrocyclic scaffold (c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro]) were explored with 14-compound and 8-compound libraries, respectively, to generate more potent, selective melanocortin receptor antagonists. Substituting diaminopropionic acid (Dap), DDap, and His at the Asn position yielded potent MC4R ligands, while replacing Ala with Ser maintained MC4R potency. Since these substitutions correlate to ASP loop residues, an additional Phe to Ala substitution was synthesized and observed to maintain MC4R potency. Seventeen compounds also possessed inverse agonist activity at the MC5R, the first report of this pharmacology. These findings are useful in develop...
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a macrocyclic agouti related protein nle4 dphe7 α melanocyte stimulating hormone chimeric scaffold produces subnanomolar melanocortin receptor ligands
Journal of Medicinal Chemistry, 2017Co-Authors: Mark D Ericson, Katie T Freeman, Sathya M Schnell, Carrie HaskellluevanoAbstract:The melanocortin system consists of five receptor subtypes, endogenous agonists, and naturally occurring antagonists. These receptors and ligands have been implicated in numerous biological pathways including processes linked to obesity and food intake. Herein, a truncation structure–activity relationship study of chimeric agouti-related protein (AGRP)/[Nle4,DPhe7]α-melanocyte stimulating hormone (NDP-MSH) ligands is reported. The tetrapeptide His-DPhe-Arg-Trp or tripeptide DPhe-Arg-Trp replaced the Arg-Phe-Phe sequence in the AGRP active loop derivative c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was the native Asn of AGRP or a diaminopropionic (Dap) acid residue previously shown to increase antagonist potency at the mMC4R. The Phe, Ala, and Dap/Asn residues were successively removed to generate a 14-member library that was assayed for agonist activity at the mouse MC1R, MC3R, MC4R, and MC5R. Two compounds possessed nanomolar agonist potency at the mMC4R, c[Pro-His-DPhe-Arg-Trp-Asn-Ala-Phe-DPro] and c...
Mark D Ericson - One of the best experts on this subject based on the ideXlab platform.
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peptoid nphe4 in agrp based c pro1 arg2 phe3 phe4 xxx5 ala6 phe7 dpro8 scaffolds maintain mouse mc4r antagonist potency
ACS Medicinal Chemistry Letters, 2020Co-Authors: Mark D Ericson, Katie T Freeman, Carrie HaskellluevanoAbstract:The melanocortin receptors are involved in numerous physiological functions and are regulated by agonists derived from the proopiomelanocortin gene transcript and two endogenous antagonists, agouti and agouti-related protein (AGRP). The key binding and functional determinant of AGRP, an MC3R and MC4R antagonist, is an Arg-Phe-Phe tripeptide sequence located on an exposed hexapeptide (Arg-Phe-Phe-Asn-Ala-Phe) loop. It has previously been observed that cyclizing this sequence through a DPro-Pro motif (c[Pro1-Arg2-Phe3-Phe4-Asn5-Ala6-Phe7-DPro8]) resulted in a macrocyclic scaffold with MC4R antagonist activity, with increased MC4R potency when a diaminopropionic acid (Dap) residue is substituted at position 5. In this report, a series of 11 single-peptoid substitutions were performed in the AGRP-derived macrocycles. While most peptoid substitutions decreased MC4R antagonist potency, it was observed that NPhe4 (compounds 4 and 11) or NDab5 (diaminobutyric acid, compound 7) maintained MC4R antagonist potency. The NPhe4 substitutions also resulted in MC5R antagonist and inverse agonist activity equipotent to the parent scaffolds. These data may be used in the design of future MC4R and MC5R antagonist leads and probes that possess increased metabolic stability due to the presence of peptoid residues.
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arg phe phe d amino acid stereochemistry scan in the macrocyclic agouti related protein antagonist scaffold c pro arg phe phe xxx ala phe dpro results in unanticipated melanocortin 1 receptor agonist profiles
ACS Chemical Neuroscience, 2018Co-Authors: Mark D Ericson, Katie T Freeman, Katlyn A Fleming, Zoe M Koerperich, Carrie HaskellluevanoAbstract:The melanocortin-3 and melanocortin-4 receptors (MC3R and MC4R), endogenous agonists derived from the proopiomelanocortin gene transcript, and naturally occurring antagonists agouti and agouti-related protein (AGRP) have been linked to biological pathways associated with energy homeostasis. The active tripeptide sequence of AGRP, Arg111-Phe112-Phe113, is located on a hypothesized β-hairpin loop. Herein, stereochemical modifications of the Arg-Phe-Phe sequence were examined in the octapeptide AGRP-derived macrocyclic scaffold c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was Asn or diaminopropionic acid (Dap). Macrocyclic peptides were synthesized with one, two, or three residues of the Arg-Phe-Phe sequence substituted with the corresponding d-isomer(s), generating a 14 compound library. While l-to-d inversions of the Arg-Phe-Phe sequence in a 20-residue AGRP-derived ligand previously resulted in agonist activity at the MC1R, MC3R, MC4R, and MC5R, only the MC1R was consistently stimulated by the macrocyclic ligands in the present study, with varying ligand potencies and efficacies observed at the MC1R. A general trend of increased MC4R antagonist potency was observed for Dap-containing compounds, while MC5R inverse agonist activity was observed for select ligands. It was observed that stereochemical modification of the Arg-Phe-Phe active tripeptide sequence was insufficient to convert melanocortin antagonist into agonists. Overall, these observations are important in the design of melanocortin ligands possessing potent and selective agonist and antagonist activities.
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arg phe phe d amino acid stereochemistry scan in the macrocyclic agouti related protein antagonist scaffold c pro arg phe phe xxx ala phe dpro results in unanticipated melanocortin 1 receptor agonist profiles
ACS Chemical Neuroscience, 2018Co-Authors: Mark D Ericson, Katie T Freeman, Katlyn A Fleming, Zoe M Koerperich, Carrie HaskellluevanoAbstract:The melanocortin-3 and melanocortin-4 receptors (MC3R and MC4R), endogenous agonists derived from the proopiomelanocortin gene transcript, and naturally occurring antagonists agouti and agouti-related protein (AGRP) have been linked to biological pathways associated with energy homeostasis. The active tripeptide sequence of AGRP, Arg111-Phe112-Phe113, is located on a hypothesized β-hairpin loop. Herein, stereochemical modifications of the Arg-Phe-Phe sequence were examined in the octapeptide AGRP-derived macrocyclic scaffold c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was Asn or diaminopropionic acid (Dap). Macrocyclic peptides were synthesized with one, two, or three residues of the Arg-Phe-Phe sequence substituted with the corresponding d-isomer(s), generating a 14 compound library. While l-to-d inversions of the Arg-Phe-Phe sequence in a 20-residue AGRP-derived ligand previously resulted in agonist activity at the MC1R, MC3R, MC4R, and MC5R, only the MC1R was consistently stimulated by the macrocycl...
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structure activity relationship studies on a macrocyclic agouti related protein agrp scaffold reveal agouti signaling protein asp residue substitutions maintain melanocortin 4 receptor antagonist potency and result in inverse agonist pharmacology at
Journal of Medicinal Chemistry, 2017Co-Authors: Mark D Ericson, Katie T Freeman, Sathya M Schnell, Katlyn A Fleming, Carrie HaskellluevanoAbstract:The melanocortin system consists of five reported receptors, agonists from the proopiomelanocortin gene transcript, and two antagonists, agouti-signaling protein (ASP) and agouti-related protein (AGRP). For both ASP and AGRP, the hypothesized Arg-Phe-Phe pharmacophores are on exposed β-hairpin loops. In this study, the Asn and Ala positions of a reported AGRP macrocyclic scaffold (c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro]) were explored with 14-compound and 8-compound libraries, respectively, to generate more potent, selective melanocortin receptor antagonists. Substituting diaminopropionic acid (Dap), DDap, and His at the Asn position yielded potent MC4R ligands, while replacing Ala with Ser maintained MC4R potency. Since these substitutions correlate to ASP loop residues, an additional Phe to Ala substitution was synthesized and observed to maintain MC4R potency. Seventeen compounds also possessed inverse agonist activity at the MC5R, the first report of this pharmacology. These findings are useful in develop...
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a macrocyclic agouti related protein nle4 dphe7 α melanocyte stimulating hormone chimeric scaffold produces subnanomolar melanocortin receptor ligands
Journal of Medicinal Chemistry, 2017Co-Authors: Mark D Ericson, Katie T Freeman, Sathya M Schnell, Carrie HaskellluevanoAbstract:The melanocortin system consists of five receptor subtypes, endogenous agonists, and naturally occurring antagonists. These receptors and ligands have been implicated in numerous biological pathways including processes linked to obesity and food intake. Herein, a truncation structure–activity relationship study of chimeric agouti-related protein (AGRP)/[Nle4,DPhe7]α-melanocyte stimulating hormone (NDP-MSH) ligands is reported. The tetrapeptide His-DPhe-Arg-Trp or tripeptide DPhe-Arg-Trp replaced the Arg-Phe-Phe sequence in the AGRP active loop derivative c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was the native Asn of AGRP or a diaminopropionic (Dap) acid residue previously shown to increase antagonist potency at the mMC4R. The Phe, Ala, and Dap/Asn residues were successively removed to generate a 14-member library that was assayed for agonist activity at the mouse MC1R, MC3R, MC4R, and MC5R. Two compounds possessed nanomolar agonist potency at the mMC4R, c[Pro-His-DPhe-Arg-Trp-Asn-Ala-Phe-DPro] and c...
Katie T Freeman - One of the best experts on this subject based on the ideXlab platform.
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peptoid nphe4 in agrp based c pro1 arg2 phe3 phe4 xxx5 ala6 phe7 dpro8 scaffolds maintain mouse mc4r antagonist potency
ACS Medicinal Chemistry Letters, 2020Co-Authors: Mark D Ericson, Katie T Freeman, Carrie HaskellluevanoAbstract:The melanocortin receptors are involved in numerous physiological functions and are regulated by agonists derived from the proopiomelanocortin gene transcript and two endogenous antagonists, agouti and agouti-related protein (AGRP). The key binding and functional determinant of AGRP, an MC3R and MC4R antagonist, is an Arg-Phe-Phe tripeptide sequence located on an exposed hexapeptide (Arg-Phe-Phe-Asn-Ala-Phe) loop. It has previously been observed that cyclizing this sequence through a DPro-Pro motif (c[Pro1-Arg2-Phe3-Phe4-Asn5-Ala6-Phe7-DPro8]) resulted in a macrocyclic scaffold with MC4R antagonist activity, with increased MC4R potency when a diaminopropionic acid (Dap) residue is substituted at position 5. In this report, a series of 11 single-peptoid substitutions were performed in the AGRP-derived macrocycles. While most peptoid substitutions decreased MC4R antagonist potency, it was observed that NPhe4 (compounds 4 and 11) or NDab5 (diaminobutyric acid, compound 7) maintained MC4R antagonist potency. The NPhe4 substitutions also resulted in MC5R antagonist and inverse agonist activity equipotent to the parent scaffolds. These data may be used in the design of future MC4R and MC5R antagonist leads and probes that possess increased metabolic stability due to the presence of peptoid residues.
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arg phe phe d amino acid stereochemistry scan in the macrocyclic agouti related protein antagonist scaffold c pro arg phe phe xxx ala phe dpro results in unanticipated melanocortin 1 receptor agonist profiles
ACS Chemical Neuroscience, 2018Co-Authors: Mark D Ericson, Katie T Freeman, Katlyn A Fleming, Zoe M Koerperich, Carrie HaskellluevanoAbstract:The melanocortin-3 and melanocortin-4 receptors (MC3R and MC4R), endogenous agonists derived from the proopiomelanocortin gene transcript, and naturally occurring antagonists agouti and agouti-related protein (AGRP) have been linked to biological pathways associated with energy homeostasis. The active tripeptide sequence of AGRP, Arg111-Phe112-Phe113, is located on a hypothesized β-hairpin loop. Herein, stereochemical modifications of the Arg-Phe-Phe sequence were examined in the octapeptide AGRP-derived macrocyclic scaffold c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was Asn or diaminopropionic acid (Dap). Macrocyclic peptides were synthesized with one, two, or three residues of the Arg-Phe-Phe sequence substituted with the corresponding d-isomer(s), generating a 14 compound library. While l-to-d inversions of the Arg-Phe-Phe sequence in a 20-residue AGRP-derived ligand previously resulted in agonist activity at the MC1R, MC3R, MC4R, and MC5R, only the MC1R was consistently stimulated by the macrocyclic ligands in the present study, with varying ligand potencies and efficacies observed at the MC1R. A general trend of increased MC4R antagonist potency was observed for Dap-containing compounds, while MC5R inverse agonist activity was observed for select ligands. It was observed that stereochemical modification of the Arg-Phe-Phe active tripeptide sequence was insufficient to convert melanocortin antagonist into agonists. Overall, these observations are important in the design of melanocortin ligands possessing potent and selective agonist and antagonist activities.
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arg phe phe d amino acid stereochemistry scan in the macrocyclic agouti related protein antagonist scaffold c pro arg phe phe xxx ala phe dpro results in unanticipated melanocortin 1 receptor agonist profiles
ACS Chemical Neuroscience, 2018Co-Authors: Mark D Ericson, Katie T Freeman, Katlyn A Fleming, Zoe M Koerperich, Carrie HaskellluevanoAbstract:The melanocortin-3 and melanocortin-4 receptors (MC3R and MC4R), endogenous agonists derived from the proopiomelanocortin gene transcript, and naturally occurring antagonists agouti and agouti-related protein (AGRP) have been linked to biological pathways associated with energy homeostasis. The active tripeptide sequence of AGRP, Arg111-Phe112-Phe113, is located on a hypothesized β-hairpin loop. Herein, stereochemical modifications of the Arg-Phe-Phe sequence were examined in the octapeptide AGRP-derived macrocyclic scaffold c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was Asn or diaminopropionic acid (Dap). Macrocyclic peptides were synthesized with one, two, or three residues of the Arg-Phe-Phe sequence substituted with the corresponding d-isomer(s), generating a 14 compound library. While l-to-d inversions of the Arg-Phe-Phe sequence in a 20-residue AGRP-derived ligand previously resulted in agonist activity at the MC1R, MC3R, MC4R, and MC5R, only the MC1R was consistently stimulated by the macrocycl...
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structure activity relationship studies on a macrocyclic agouti related protein agrp scaffold reveal agouti signaling protein asp residue substitutions maintain melanocortin 4 receptor antagonist potency and result in inverse agonist pharmacology at
Journal of Medicinal Chemistry, 2017Co-Authors: Mark D Ericson, Katie T Freeman, Sathya M Schnell, Katlyn A Fleming, Carrie HaskellluevanoAbstract:The melanocortin system consists of five reported receptors, agonists from the proopiomelanocortin gene transcript, and two antagonists, agouti-signaling protein (ASP) and agouti-related protein (AGRP). For both ASP and AGRP, the hypothesized Arg-Phe-Phe pharmacophores are on exposed β-hairpin loops. In this study, the Asn and Ala positions of a reported AGRP macrocyclic scaffold (c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro]) were explored with 14-compound and 8-compound libraries, respectively, to generate more potent, selective melanocortin receptor antagonists. Substituting diaminopropionic acid (Dap), DDap, and His at the Asn position yielded potent MC4R ligands, while replacing Ala with Ser maintained MC4R potency. Since these substitutions correlate to ASP loop residues, an additional Phe to Ala substitution was synthesized and observed to maintain MC4R potency. Seventeen compounds also possessed inverse agonist activity at the MC5R, the first report of this pharmacology. These findings are useful in develop...
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a macrocyclic agouti related protein nle4 dphe7 α melanocyte stimulating hormone chimeric scaffold produces subnanomolar melanocortin receptor ligands
Journal of Medicinal Chemistry, 2017Co-Authors: Mark D Ericson, Katie T Freeman, Sathya M Schnell, Carrie HaskellluevanoAbstract:The melanocortin system consists of five receptor subtypes, endogenous agonists, and naturally occurring antagonists. These receptors and ligands have been implicated in numerous biological pathways including processes linked to obesity and food intake. Herein, a truncation structure–activity relationship study of chimeric agouti-related protein (AGRP)/[Nle4,DPhe7]α-melanocyte stimulating hormone (NDP-MSH) ligands is reported. The tetrapeptide His-DPhe-Arg-Trp or tripeptide DPhe-Arg-Trp replaced the Arg-Phe-Phe sequence in the AGRP active loop derivative c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was the native Asn of AGRP or a diaminopropionic (Dap) acid residue previously shown to increase antagonist potency at the mMC4R. The Phe, Ala, and Dap/Asn residues were successively removed to generate a 14-member library that was assayed for agonist activity at the mouse MC1R, MC3R, MC4R, and MC5R. Two compounds possessed nanomolar agonist potency at the mMC4R, c[Pro-His-DPhe-Arg-Trp-Asn-Ala-Phe-DPro] and c...
Andrzej Wilczynski - One of the best experts on this subject based on the ideXlab platform.
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discovery of a β hairpin octapeptide c pro arg phe phe dap ala phe dpro mimetic of agouti related protein 87 132 agrp 87 132 with equipotent mouse melanocortin 4 receptor mmc4r antagonist pharmacology
Journal of Medicinal Chemistry, 2015Co-Authors: Mark D Ericson, Andrzej Wilczynski, Nicholas B. Sorensen, Zhimin Xiang, Carrie HaskellluevanoAbstract:Agouti-related protein (AGRP) is a potent orexigenic peptide that antagonizes the melanocortin-3 and -4 receptors (MC3R and MC4R). While the C-terminal domain of AGRP, AGRP(87-132), is equipotent to the full-length peptide, further truncation decreases potency at the MC3R and MC4R. Herein, we report AGRP-derived peptides designed to mimic the active β-hairpin secondary structure that contains the hypothesized Arg-Phe-Phe pharmacophore. The most potent scaffold, c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro], comprised the hexa-peptide β-hairpin loop from AGRP cyclized through a DPro-Pro motif. A 20 compound library was synthesized from this scaffold for further structure-activity relationship studies. The most potent peptide from this library was an asparagine to diaminopropionic acid substitution that possessed sub-nanomolar antagonist activity at the mMC4R and was greater than 160-fold selective for the mMC4R versus the mMC3R. The reported ligands may serve as probes to characterize the melanocortin receptors in vivo and leads in the development of novel therapeutics.
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Discovery of a β-Hairpin Octapeptide, c[Pro-Arg-Phe-Phe-Dap-Ala-Phe-DPro], Mimetic of Agouti-Related Protein(87-132) [AGRP(87-132)] with Equipotent Mouse Melanocortin-4 Receptor (mMC4R) Antagonist Pharmacology.
Journal of medicinal chemistry, 2015Co-Authors: Mark D Ericson, Andrzej Wilczynski, Nicholas B. Sorensen, Zhimin Xiang, Carrie Haskell-luevanoAbstract:Agouti-related protein (AGRP) is a potent orexigenic peptide that antagonizes the melanocortin-3 and -4 receptors (MC3R and MC4R). While the C-terminal domain of AGRP, AGRP(87–132), is equipotent to the full-length peptide, further truncation decreases potency at the MC3R and MC4R. Herein, we report AGRP-derived peptides designed to mimic the active β-hairpin secondary structure that contains the hypothesized Arg-Phe-Phe pharmacophore. The most potent scaffold, c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro], comprised the hexa-peptide β-hairpin loop from AGRP cyclized through a DPro–Pro motif. A 20 compound library was synthesized from this scaffold for further structure–activity relationship studies. The most potent peptide from this library was an asparagine to diaminopropionic acid substitution that possessed sub-nanomolar antagonist activity at the mMC4R and was greater than 160-fold selective for the mMC4R versus the mMC3R. The reported ligands may serve as probes to characterize the melanocortin receptors in v...
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structure activity relationships of the unique and potent agouti related protein agrp melanocortin chimeric tyr c β asp his dphe arg trp asn ala phe dpr tyr nh2 peptide template
Journal of Medicinal Chemistry, 2005Co-Authors: Andrzej Wilczynski, Joseph W Scott, Krista R Wilson, And Arthur S Edison, Carrie HaskellluevanoAbstract:The melanocortin receptor system consists of endogenous agonists, antagonists, G-protein coupled receptors, and auxiliary proteins that are involved in the regulation of complex physiological functions such as energy and weight homeostasis, feeding behavior, inflammation, sexual function, pigmentation, and exocrine gland function. Herein, we report the structure−activity relationship (SAR) of a new chimeric hAGRP−melanocortin agonist peptide template Tyr-c[β-Asp-His-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH2 that was characterized using amino acids previously reported in other melanocortin agonist templates. Twenty peptides were examined in this study, and six peptides were selected for 1H NMR and computer-assisted molecular modeling structural analysis. The most notable results include the identification that modification of the chimeric template at the His position with Pro and Phe resulted in ligands that were nM mouse melanocortin-3 receptor (mMC3R) antagonists and nM mouse melanocortin-4 receptor (mMC4R) ...
Katlyn A Fleming - One of the best experts on this subject based on the ideXlab platform.
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arg phe phe d amino acid stereochemistry scan in the macrocyclic agouti related protein antagonist scaffold c pro arg phe phe xxx ala phe dpro results in unanticipated melanocortin 1 receptor agonist profiles
ACS Chemical Neuroscience, 2018Co-Authors: Mark D Ericson, Katie T Freeman, Katlyn A Fleming, Zoe M Koerperich, Carrie HaskellluevanoAbstract:The melanocortin-3 and melanocortin-4 receptors (MC3R and MC4R), endogenous agonists derived from the proopiomelanocortin gene transcript, and naturally occurring antagonists agouti and agouti-related protein (AGRP) have been linked to biological pathways associated with energy homeostasis. The active tripeptide sequence of AGRP, Arg111-Phe112-Phe113, is located on a hypothesized β-hairpin loop. Herein, stereochemical modifications of the Arg-Phe-Phe sequence were examined in the octapeptide AGRP-derived macrocyclic scaffold c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was Asn or diaminopropionic acid (Dap). Macrocyclic peptides were synthesized with one, two, or three residues of the Arg-Phe-Phe sequence substituted with the corresponding d-isomer(s), generating a 14 compound library. While l-to-d inversions of the Arg-Phe-Phe sequence in a 20-residue AGRP-derived ligand previously resulted in agonist activity at the MC1R, MC3R, MC4R, and MC5R, only the MC1R was consistently stimulated by the macrocycl...
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arg phe phe d amino acid stereochemistry scan in the macrocyclic agouti related protein antagonist scaffold c pro arg phe phe xxx ala phe dpro results in unanticipated melanocortin 1 receptor agonist profiles
ACS Chemical Neuroscience, 2018Co-Authors: Mark D Ericson, Katie T Freeman, Katlyn A Fleming, Zoe M Koerperich, Carrie HaskellluevanoAbstract:The melanocortin-3 and melanocortin-4 receptors (MC3R and MC4R), endogenous agonists derived from the proopiomelanocortin gene transcript, and naturally occurring antagonists agouti and agouti-related protein (AGRP) have been linked to biological pathways associated with energy homeostasis. The active tripeptide sequence of AGRP, Arg111-Phe112-Phe113, is located on a hypothesized β-hairpin loop. Herein, stereochemical modifications of the Arg-Phe-Phe sequence were examined in the octapeptide AGRP-derived macrocyclic scaffold c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was Asn or diaminopropionic acid (Dap). Macrocyclic peptides were synthesized with one, two, or three residues of the Arg-Phe-Phe sequence substituted with the corresponding d-isomer(s), generating a 14 compound library. While l-to-d inversions of the Arg-Phe-Phe sequence in a 20-residue AGRP-derived ligand previously resulted in agonist activity at the MC1R, MC3R, MC4R, and MC5R, only the MC1R was consistently stimulated by the macrocyclic ligands in the present study, with varying ligand potencies and efficacies observed at the MC1R. A general trend of increased MC4R antagonist potency was observed for Dap-containing compounds, while MC5R inverse agonist activity was observed for select ligands. It was observed that stereochemical modification of the Arg-Phe-Phe active tripeptide sequence was insufficient to convert melanocortin antagonist into agonists. Overall, these observations are important in the design of melanocortin ligands possessing potent and selective agonist and antagonist activities.
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structure activity relationship studies on a macrocyclic agouti related protein agrp scaffold reveal agouti signaling protein asp residue substitutions maintain melanocortin 4 receptor antagonist potency and result in inverse agonist pharmacology at
Journal of Medicinal Chemistry, 2017Co-Authors: Mark D Ericson, Katie T Freeman, Sathya M Schnell, Katlyn A Fleming, Carrie HaskellluevanoAbstract:The melanocortin system consists of five reported receptors, agonists from the proopiomelanocortin gene transcript, and two antagonists, agouti-signaling protein (ASP) and agouti-related protein (AGRP). For both ASP and AGRP, the hypothesized Arg-Phe-Phe pharmacophores are on exposed β-hairpin loops. In this study, the Asn and Ala positions of a reported AGRP macrocyclic scaffold (c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro]) were explored with 14-compound and 8-compound libraries, respectively, to generate more potent, selective melanocortin receptor antagonists. Substituting diaminopropionic acid (Dap), DDap, and His at the Asn position yielded potent MC4R ligands, while replacing Ala with Ser maintained MC4R potency. Since these substitutions correlate to ASP loop residues, an additional Phe to Ala substitution was synthesized and observed to maintain MC4R potency. Seventeen compounds also possessed inverse agonist activity at the MC5R, the first report of this pharmacology. These findings are useful in develop...