Joseph W. Scott
University of Florida
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Featured researches published by Joseph W. Scott.
Peptides | 2003
Christine G. Joseph; Andrzej Wilczynski; Jerry Ryan Holder; Zhimin Xiang; Rayna M. Bauzo; Joseph W. Scott; Carrie Haskell-Luevano
Agouti-related protein (AGRP) is one of only two known endogenous antagonists of G-protein coupled receptors (GPCRs). Specifically, AGRP antagonizes the brain melanocortin-3 and -4 receptors involved in energy homeostasis, regulation of feeding behavior, and obesity. Alpha-melanocyte stimulating hormone (alpha-MSH) is one of the known endogenous agonists for these receptors. It has been hypothesized that the Arg-Phe-Phe (111-113) human AGRP amino acids may be mimicking the melanocortin agonist Phe-Arg-Trp (7-9) residue interactions with the melanocortin receptors that are important for both receptor molecular recognition and stimulation. To test this hypothesis, we generated thirteen chimeric peptide ligands based upon the melanocortin agonist peptides NDP-MSH (Ac-Ser-Tyr-Ser-Nle4-Glu-His-DPhe-Arg-Trp-Gly-Lys-Pro-Val-NH2) and MTII (Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2). In these chimeric ligands, the agonist DPhe-Arg-Trp amino acids were replaced by the AGRP Arg-Phe-Phe residues, and resulted in agonist activity at the mouse melanocortin receptors (mMC1R and mMC3-5Rs), supporting the hypothesis that the AGRP antagonist ligand Arg-Phe-Phe residues mimic the agonist Phe-Arg-Trp amino acids. Interestingly, the Ac-Ser-Tyr-Ser-Nle4-Glu-His-Arg-DPhe-Phe-Gly-Lys-Pro-Val-NH2 peptide possessed 7 nM mMC1R agonist potency, and is 850-fold selective for the mMC1R versus the mMC3R, 2300-fold selective for the mMC1R versus the mMC4R, and 60-fold selective for the MC1R versus the mMC5R, resulting in the discovery of a new peptide template for the design of melanocortin receptor selective ligands.
Peptides | 2010
Christine G. Joseph; Hua Yao; Joseph W. Scott; Nicholas B. Sorensen; Rebecca N. Marnane; Kathleen G. Mountjoy; Carrie Haskell-Luevano
The melanocortin system has been implicated in a multitude of physiological pathways including obesity, satiety, energy homeostasis, sexual behavior, pigmentation, sodium regulation, hypertension, and many others. Based upon studies of the endogenous melanocortin receptor agonists at the cloned human melanocortin receptor proteins, it was concluded that the γ-MSH related agonist ligands are selective for the MC3 versus the MC4 and MC5 receptors. In attempts to understand and identify the specific amino acids of γ₂-MSH important for MC3R selectivity, we have performed N- and C-terminal truncation studies and pharmacologically characterized twenty-eight ligands at the mouse MC1 and MC3-5 melanocortin receptors. The C-terminal Trp-Asp⁹-Arg¹⁰-Phe¹¹ residues are important for nM potency at the mMC3R and the Arg⁷-Trp⁸ residues are important for mMC5R nM potency. We observed the unanticipated results that several of the C-terminal truncated analogs possessed nM agonist potency at the mMC3 and mMC5Rs which lead us to perform a comparative side-by-side study of the mouse and human MC5R. These data resulted in μM γ₂-MSH analog potency at the hMC5R, consistent with previous reports, however at the mMC5R, nM γ₂-MSH analog potency was observed. Thus, these data support the hypothesis of important species specific differences in γ-MSH related ligand potency at the rodent versus human MC5R subtype that is critical for the interpretation of in vivo rodent physiological studies. These results prompted us to examine the affects of a peripherally administered melanocortin agonist on hypothalamic gene expression levels of the MC3R, MC4R, and MC5R. The super potent non-selective NDP-MSH agonist was administered i.p. and resulted in significantly decreased levels of mMC3R and mMC5R hypothalamic mRNA versus saline control. These data provide for the first time data demonstrating peripherally administered NDP-MSH can modify hypothalamic melanocortin receptor expression levels.
ACS Chemical Neuroscience | 2018
Aleksandar Todorovic; Cody J. Lensing; Jerry Ryan Holder; Joseph W. Scott; Nicholas B. Sorensen; Carrie Haskell-Luevano
The melanocortin system regulates an array of diverse physiological functions including pigmentation, feeding behavior, energy homeostasis, cardiovascular regulation, sexual function, and steroidogenesis. Endogenous melanocortin agonist ligands all possess the minimal messaging tetrapeptide sequence His-Phe-Arg-Trp. Based on this endogenous sequence, the Ac-His1-dPhe2-Arg3-Trp4-NH2 tetrapeptide has previously been shown to be a useful scaffold when utilizing traditional positional scanning approaches to modify activity at the various melanocortin receptors (MC1-5R). The study reported herein was undertaken to evaluate a double simultaneous substitution strategy as an approach to further diversify the Ac-His1-dPhe2-Arg3-Trp4-NH2 tetrapeptide with concurrent introduction of natural and unnatural amino acids at positions 1, 2, or 4, as well as an octanoyl residue at the N-terminus. The designed library includes the following combinations: (A) double simultaneous substitution at capping group position (Ac) together with position 1, 2, or 4, (B) double simultaneous substitution at positions 1 and 2, (C) double simultaneous substitution at positions 1 and 4, and (D) double simultaneous substitution at positions 2 and 4. Several lead ligands with unique pharmacologies were discovered in the current study including antagonists targeting the neuronal mMC3R with minimal agonist activity and ligands with selective profiles for the various melanocortin subtypes. The results suggest that the double simultaneous substitution strategy is a suitable approach in altering melanocortin receptor potency or selectivity or converting agonists into antagonists and vice versa.
Journal of Medicinal Chemistry | 2004
Andrzej Wilczynski; Xiang S. Wang; Christine G. Joseph; Zhimin Xiang; Rayna M. Bauzo; Joseph W. Scott; Nicholas B. Sorensen; Amanda M. Shaw; William J. Millard; Nigel G. J. Richards; Carrie Haskell-Luevano
Journal of Bacteriology | 2002
Joseph W. Scott; Madeline E. Rasche
Journal of Medicinal Chemistry | 2005
Aleksandar Todorovic; Jerry Ryan Holder; Rayna M. Bauzo; Joseph W. Scott; Renny Kavanagh; Zalfa A. Abdel-Malek; Carrie Haskell-Luevano
Bioorganic & Medicinal Chemistry Letters | 2003
Jerry Ryan Holder; Rayna M. Bauzo; Zhimin Xiang; Joseph W. Scott; Carrie Haskell-Luevano
Journal of Medicinal Chemistry | 2005
Andrzej Wilczynski; Krista R. Wilson; Joseph W. Scott; and Arthur S. Edison; Carrie Haskell-Luevano
Journal of Peptide Research | 2004
Aleksandar Todorovic; Jerry Ryan Holder; Joseph W. Scott; Carrie Haskell-Luevano
Journal of Medicinal Chemistry | 2004
Christine G. Joseph; Xiang S. Wang; Joseph W. Scott; Rayna M. Bauzo; Zhimin Xiang; Nigel G. J. Richards; Carrie Haskell-Luevano