Identification of Tetrapeptides from a Mixture Based Positional Scanning Library That Can Restore nM Full Agonist Function of the L106P, I69T, I102S, A219V, C271Y, and C271R Human Melanocortin-4 Polymorphic Receptors (hMC4Rs)

Human obesity has been linked to genetic factors and single nucleotide polymorphisms (SNPs). Melanocortin-4 receptor (MC4R) SNPs have been associated with up to 6% frequency in morbidly obese children and adults. A potential therapy for individuals possessing such genetic modifications is the identification of molecules that can restore proper receptor signaling and function. These compounds could serve as personalized medications improving quality of life issues as well as alleviating diseases symptoms associated with obesity including type 2 diabetes. Several hMC4 SNP receptors have been pharmacologically characterized in vitro to have a decreased, or a lack of response, to endogenous agonists such as α-, β-, and γ2-melanocyte stimulating hormones (MSH) and adrenocorticotropin hormone (ACTH). Herein we report the use of a mixture based positional scanning combinatorial tetrapeptide library to discover molecules with nM full agonist potency and efficacy to the L106P, I69T, I102S, A219V, C271Y, and C271R hMC4Rs. The most potent compounds at all these hMC4R SNPs include Ac-His-(pI)DPhe-Tic-(pNO2)DPhe-NH2, Ac-His-(pCl)DPhe-Tic-(pNO2)DPhe-NH2, Ac-His-(pCl)DPhe-Arg-(pI)Phe-NH2, and Ac-Arg-(pCl)DPhe-Tic-(pNO2)DPhe-NH2, revealing new ligand pharmacophore models for melanocortin receptor drug design strategies

1,4-Disubstituted-[1,2,3]triazolyl-Containing Analogues of MT-II: Design, Synthesis, Conformational Analysis, and Biological Activity

Side chain-to-side chain cyclizations represent a strategy to select a family of bioactive conformations by reducing the entropy and enhancing the stabilization of functional ligand-induced receptor conformations. This structural manipulation contributes to increased target specificity, enhanced biological potency, improved pharmacokinetic properties, increased functional potency, and lowered metabolic susceptibility. The CuI-catalyzed azide–alkyne 1,3-dipolar Huisgen’s cycloaddition, the prototypic click reaction, presents a promising opportunity to develop a new paradigm for an orthogonal bioorganic and intramolecular side chain-to-side chain cyclization. In fact, the proteolytic stable 1,4- or 4,1-disubstituted [1,2,3]triazolyl moiety is isosteric with the peptide bond and can function as a surrogate of the classical side chain-to-side chain lactam forming bridge. Herein we report the design, synthesis, conformational analysis, and functional biological activity of a series of i-to-i+5 1,4- and 4,1-disubstituted [1,2,3]triazole-bridged cyclopeptides derived from MT-II, the homodetic Asp5 to Lys10 side chain-to-side chain bridged heptapeptide, an extensively studied agonist of melanocortin receptors

Melanocortin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Melanocortin receptors (provisional nomenclature as recommended by NC-IUPHAR [36]) are activated by members of the melanocortin family (α-MSH, β-MSH and γ-MSH forms; δ form is not found in mammals) and adrenocorticotrophin (ACTH). Endogenous antagonists include agouti and agouti-related protein. ACTH(1-24) was approved by the US FDA as a diagnostic agent for adrenal function test, whilst NDP-MSH was approved by EMA for the treatment of erythropoietic protoporphyria. Several synthetic melanocortin receptor agonists are under clinical development

Melanocortin receptors in GtoPdb v.2023.1

Melanocortin receptors (provisional nomenclature as recommended by NC-IUPHAR [41]) are activated by members of the melanocortin family (α-MSH, β-MSH and γ-MSH forms; δ form is not found in mammals) and adrenocorticotrophin (ACTH). Endogenous antagonists include agouti and agouti-related protein. ACTH(1-24) was approved by the US FDA as a diagnostic agent for adrenal function test. setmelanotide was approved by the US FDA for weight management in patients with POMC, PCSK1 or LEPR defiency, bremelanotide was approved by the US FDA for generalized hypoactive sexual desire disorder in premenopausal women, and NDP-MSH (afamelanotide) was approved by the EMA for the treatment of erythropoietic protoporphyria. Several synthetic melanocortin receptor agonists are under clinical development

Melanocortin receptors in GtoPdb v.2021.3

Melanocortin receptors (provisional nomenclature as recommended by NC-IUPHAR [41]) are activated by members of the melanocortin family (α-MSH, β-MSH and γ-MSH forms; δ form is not found in mammals) and adrenocorticotrophin (ACTH). Endogenous antagonists include agouti and agouti-related protein. ACTH(1-24) was approved by the US FDA as a diagnostic agent for adrenal function test, whilst NDP-MSH was approved by EMA for the treatment of erythropoietic protoporphyria. Several synthetic melanocortin receptor agonists are under clinical development

The melanocortin pathway and energy homeostasis: From discovery to obesity therapy.

BACKGROUND: Over the past 20 years, insights from human and mouse genetics have illuminated the central role of the brain leptin-melanocortin pathway in controlling mammalian food intake, with genetic disruption resulting in extreme obesity, and more subtle polymorphic variations influencing the population distribution of body weight. At the end of 2020, the U.S. Food and Drug Administration (FDA) approved setmelanotide, a melanocortin 4 receptor agonist, for use in individuals with severe obesity due to either pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency. SCOPE OF REVIEW: Herein, we chart the melanocortin pathway's history, explore its pharmacology, genetics, and physiology, and describe how a neuropeptidergic circuit became an important druggable obesity target. MAJOR CONCLUSIONS: Unravelling the genetics of the subset of severe obesity has revealed the importance of the melanocortin pathway in appetitive control; coupling this with studying the molecular pharmacology of compounds that bind melanocortin receptors has brought a new obesity drug to the market. This process provides a drug discovery template for complex disorders, which for setmelanotide took 25 years to transform from a single gene into an approved drug

Molecular Mechanism of the Constitutive Activation of the L250Q Human Melanocortin-4 Receptor Polymorphism †

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65471/1/j.1747-0285.2006.00362.x.pd

Conformational and topographical studies of alpha-melanotropin "message" sequence and molecular modeling of the hMC1R melanocortin receptor.

The exciting and intriguing biological effects associated with amelanocyte stimulating hormone, α-MSH, have initiated a variety of studies to identify the biologically important conformations of the backbone and sidechains structures. To further investigate the topology of the critical "message" residues, several bicyclic (sidechain-to-sidechain) and x¹ restricted peptides have been synthesized and biologically examined, and selected analogues have been studied by NMR techniques and by theoretical molecular modeling studies. Bicyclic melanotropic peptides possessing the central sequence, Cys⁴-Asp⁵-His⁶-DPhe⁷-Arg⁸-Trp⁹-Cys¹⁰-Lys¹¹, exhibited nearly identical nanomolar biological potencies in the lizard skin bioassay. Molecular modeling studies suggested the hypothesis of incomplete receptor binding by either the His or Trp residue as being responsible for the decrease in potencies relative to a-MSH, and the parent monocyclic peptides from which these bicyclic peptides were designed. This hypothesis is further supported by twodimensional NMR studies of a representative bicyclic peptide, Ac-Cys⁴-Asp⁵-His⁶-DPhe⁷-Arg⁸-Trp⁹-Cys¹⁰-Lys¹¹-NH₂. Peptides synthesized to probe the topographical space of the tryptophan residue at position nine provided extraordinary results regarding the biological phenomena of prolongation. These peptides were based on the template, Ac-Nle⁴-Asp⁵-His⁶-DPhe⁷-Arg⁸-Xaa⁹-Lys¹⁰-NH₂, where Xaa consists of the four isomers of β-MeTrp, DTrp , and L- or D-TCA residues. Some of these peptides were selected for studies on the cloned hMC1 melanocortin receptor. These studies resulted in a partial hypothesis accounting for the prolonged biological activities observed in other physiological assay systems. Conformational analysis by solution 20 NMR techniques revealed similar peptide backbone secondary structure features with main differences of structure occurring in the sidechain x¹ space. The implications and results are discussed. Homology-based molecular modeling of the hMC1 melanocortin receptor was also undertaken and provided evidence for ligand-receptor interactions which are being tested by receptor mutagenesis studies. This three-dimensional computer model provides an opportunity to probe detail chemical ligand-receptor interactions and further study differences in biological activities and biological mechanisms

Advances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery: A Themed Issue Honoring Professor Victor J. Hruby on the Occasion of His 80th Birthday

Advances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery is a book dedicated to Prof. Victor J. Hruby on the occasion of his 80th birthday. This book includes twenty contributions from authors representing diverse multidisciplinary fields of scientific expertise, and is focused on the extraordinary potential of peptides and peptidomimetics as a surging therapeutic modality and as tools for basic research and technology development