SETMELANOTIDE - 20 mg

STRUCTURE

Sequence: Ac-Arg-Cys(1)-D-Ala-His-D-Phe-Arg-Trp-Cys(1)-NH2  

with Disulfide bonds into a ring as explained below:  N2-acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophyl-L-cysteinamide, cyclic (2-8)-disulfide

Molecular Formula: C₄₉H₆₈N₁₈O₉S₂

Molecular Weight: 1117.31 g/mol

PubChem CID: 11993702

Peptide purity: greater than 98%

Other details: No TFA Salt, No Mannitol

Storage: Lyophilized peptide must be stored at -20°C and peptide solution at 4°C. 

Setmelanotide has  low oral and excellent subcutaneous bioavailability.

DESCRITPION

Setmelanotide is the first available treatment for pro-opiomelanocortin, proprotein subilisin/kexin type 1, or leptin deficiencies. 

It is an agonist of the melanocortin 4 receptor. Earlier attempts at agonizing MC4R (such as LY2112688) lead to successful weight loss, but also an increase in blood pressure and heart rate.  

Grehlin and other hunger signals from the gastrointestinal tract stimulate orexigenic neurons, stimulating the release of agouti-related protein. Agouti-related protein inhibits melanocortin 4 receptor (MC4R) activation until satiety signals such as insulin or leptin stimulate anorexigenic neurons. Insulin and leptin stimulate production of the POMC-derived melanocortin peptide α-melanocyte simulating hormone, which is a ligand of MC4R. 

Orexigenic and anorexigenic neurons contain prohormone convertase 1/3 (PC1/3), which is encoded by the gene proprotein subtilisin/kexin type 1. PC1/3 preforms activation cleavage of a number of peptide hormone precursors, including α-melanocyte simulating hormone. 

Setmelanotide is a pro-opiomelanocortin derived peptide that is an agonist of MC4R. It is an approximately 20-fold more potent agonist of MC4R than endogenous α-melanocyte stimulating hormone, with an EC50 of 0.27 nM. By directly agonizing MC4R, upstream genetic deficiencies in the MC4R signalling pathway cannot inhibit satiety, food intake is decreased, and weight loss is achieved. 

MC4R is a 332 amino acid G-protein coupled receptor (G-PCR). Although the lack of cardiovascular adverse effects with setmelanotide treatment are not well understood, it is believed that earlier MC4R antagonists activated multiple G-protein signalling pathways. Earlier drugs that targeted G-PCRs either bound with high affinity to the highly conserved orthosteric binding site, or with high specificity to less conserved allosteric sites. Setmelanotide is an atypical bitopic ligand that interacts with both the orthosteric and putative allosteric binding site, allowing for both high affinity and specificity

REFERENCES

K. Clément et al., "Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials" [PubMed]

A. Markham "Setmelanotide: First Approval" [PubMed]

A.M. Haqq et al., "Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alström syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period" [PubMed]

P- Khunen et al., "Quality of life outcomes in two phase 3 trials of setmelanotide in patients with obesity due to LEPR or POMC deficiency" [PubMed]

H. Pressley et al., "Setmelanotide: A Novel Targeted Treatment for Monogenic Obesity" [PubMed]

Tinh-Hai Collet et al., "Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency" [PubMed]

R. Haws et al., "Effect of setmelanotide, a melanocortin-4 receptor agonist, on obesity in Bardet-Biedl syndrome" [PubMed]

D.H. Ryan "Next Generation Antiobesity Medications: Setmelanotide, Semaglutide, Tirzepatide and Bimagrumab: What do They Mean for Clinical Practice?" [PubMed]

M.M. Hammad et al., "Structural analysis of setmelanotide binding to MC4R variants in comparison to wild-type receptor" [PubMed]

A. Kamermans et al., "Setmelanotide, a Novel, Selective Melanocortin Receptor-4 Agonist Exerts Anti-inflammatory Actions in Astrocytes and Promotes an Anti-inflammatory Macrophage Phenotype" [PubMed]

B.A. Falls et al., "Insights into the Allosteric Mechanism of Setmelanotide (RM-493) as a Potent and First-in-Class Melanocortin-4 Receptor (MC4R) Agonist To Treat Rare Genetic Disorders of Obesity through an in Silico Approach" [PubMed]

N. Reininghaus et al., "A Setmelanotide-like Effect at MC4R Is Achieved by MC4R Dimer Separation" [PubMed]

M. Tauber "Setmelanotide for controlling weight and hunger in Bardet-Biedl syndrome" [PubMed]

R.M. Haws et al., "The efficacy and safety of setmelanotide in individuals with Bardet-Biedl syndrome or Alström syndrome: Phase 3 trial design" [PMC]

M. Wabitsch et al., "Understanding the Patient Experience of Hunger and Improved Quality of Life with Setmelanotide Treatment in POMC and LEPR Deficiencies" [PubMed]

DISCLAIMER

This product is intendend for lab research and development use only. These studies are performed outside of the body. This product is not medicines or drugs and has not been approved by the FDA or EMA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law. This product should only be handled by licensed, qualified professionals. 

All product information provided on this website is for informational and educational purposes only.