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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
Chemical Compound Review

Acth (6-9)     (2S)-2-[[(2S)-2-[[(2S)-2- amino-3-[4-[(2S)...

Synonyms: AC1Q5DWV, AR-1F9084, AR-1F9085, AC1L4O63, 4289-02-5, ...
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High impact information on His-phe-arg-trp-

  • All the endogenous melanocortin agonist ligands possess the conserved His-Phe-Arg-Trp tetrapeptide sequence that is postulated to be important for melanocortin receptor molecular recognition and stimulation [1].
  • It has been shown by extensive studies that alpha-MSH bioactivity is critically dependent on the core or central tetrapeptide sequence, His-Phe-Arg-Trp, however with poor selectivity for the human MC3R-MC5R [2].
  • To probe the receptor active conformation of the pharmacophore His-Phe-Arg-Trp in gamma-MSH, two different series of gamma-MSH analogues have been designed and synthesized and their biological activities determined at hMC3R, hMC4R, and hMC5R [3].
  • The endogenous melanocortin agonists contain the putative message sequence "His-Phe-Arg-Trp," postulated to be important for melanocortin receptor molecular recognition and stimulation [4].
  • All the endogenous (POMC-derived) melanocortin agonists contain the putative message sequence "His-Phe-Arg-Trp." Herein, we report 12 tetrapeptides, based upon the template Ac-His(6)-DPhe(7)-Arg(8)-Trp(9)-NH(2) (alpha-MSH numbering) that have been modified at the Arg(8) position by neutral, basic, or acidic amino acid side chains [5].

Biological context of His-phe-arg-trp-

  • The data show that it is possible for a beta turn to exist in the ring portion of this molecule which contains the melanocortin conserved sequence - His-Phe-Arg-Trp-, even though the lowest energy conformers lack a beta turn [6].
  • The core sequence (His-Phe-Arg-Trp) is conserved in several species and is considered as the primary active site or "message sequence". Attempts have been made to design conformationally constrained cyclic analogs containing the message sequence to improve the activity [7].

Anatomical context of His-phe-arg-trp-

  • The conserved core of melanocyte stimulating hormones (MSH), His-Phe-Arg-Trp, was probed by comparing a cyclic pentapeptide containing His-DPhe-Arg-Trp, with three structurally similar cyclic peptides, that lacked the His residue [8].

Associations of His-phe-arg-trp- with other chemical compounds


Gene context of His-phe-arg-trp-

  • These data demonstrate that the His-Phe-Arg-Trp message sequence of the melanocortin peptides does not bind and stimulate each melanocortin receptor in a similar fashion, as previously hypothesized [10].
  • For these peptides, the affinity and activity at all three human receptors (MC3R, MC4R and MC5R) decreased significantly, demonstrating that the His-Phe-Arg-Trp sequence in gamma-MSH is important for activity at these three melanocortin receptors [11].
  • The melanocortins form a family of pro-opiomelanocortin-derived peptides that have the melanocyte-stimulating hormone (MSH) core sequence, His-Phe-Arg-Trp, in common [12].
  • These peptides incorporate modifications of the melanocortin core amino acids His-Phe-Arg-Trp by using the cyclic lactam templates of the lead structures MTII and SHU9119 [13].


  1. N-terminal fatty acylated His-dPhe-Arg-Trp-NH(2) tetrapeptides: influence of fatty acid chain length on potency and selectivity at the mouse melanocortin receptors and human melanocytes. Todorovic, A., Holder, J.R., Bauzo, R.M., Scott, J.W., Kavanagh, R., Abdel-Malek, Z., Haskell-Luevano, C. J. Med. Chem. (2005) [Pubmed]
  2. Structure-activity relationships of novel cyclic alpha-MSH/beta-MSH hybrid analogues that lead to potent and selective ligands for the human MC3R and human MC5R. Balse-Srinivasan, P., Grieco, P., Cai, M., Trivedi, D., Hruby, V.J. J. Med. Chem. (2003) [Pubmed]
  3. Structure-activity relationships of gamma-MSH analogues at the human melanocortin MC3, MC4, and MC5 receptors. Discovery of highly selective hMC3R, hMC4R, and hMC5R analogues. Balse-Srinivasan, P., Grieco, P., Cai, M., Trivedi, D., Hruby, V.J. J. Med. Chem. (2003) [Pubmed]
  4. Structure-activity relationships of the melanocortin tetrapeptide Ac-His-D-Phe-Arg-Trp-NH2 at the mouse melanocortin receptors. 4. Modifications at the Trp position. Holder, J.R., Xiang, Z., Bauzo, R.M., Haskell-Luevano, C. J. Med. Chem. (2002) [Pubmed]
  5. Structure-activity relationships of the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH2 at the mouse melanocortin receptors. Part 3: modifications at the Arg position. Holder, J.R., Xiang, Z., Bauzo, R.M., Haskell-Luevano, C. Peptides (2003) [Pubmed]
  6. Molecular modelling of beta turns in a cyclic melanotropin. Chan, N.C., Branch, S.K., Moss, S.H., Pouton, C.W. J. Pharm. Pharmacol. (1996) [Pubmed]
  7. Activity and conformation of a cyclic heptapeptide possessing the message sequence His-Phe-Arg-Trp of alpha-melanotropin. Desai, P., Prachand, M., Coutinho, E., Saran, A., Bodi, J., Süli-Vargha, H. Int. J. Biol. Macromol. (2002) [Pubmed]
  8. Design of new small cyclic melanocortin receptor-binding peptides using molecular modelling: Role of the His residue in the melanocortin peptide core. Prusis, P., Muceniece, R., Mutule, I., Mutulis, F., Wikberg, J.E. European journal of medicinal chemistry. (2001) [Pubmed]
  9. Sturgeon proopiomelanocortin has a remnant of gamma-melanotropin. Amemiya, Y., Takahashi, A., Dores, R.M., Kawauchi, H. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  10. Discovery of prototype peptidomimetic agonists at the human melanocortin receptors MC1R and MC4R. Haskell-Luevano, C., Hendrata, S., North, C., Sawyer, T.K., Hadley, M.E., Hruby, V.J., Dickinson, C., Gantz, I. J. Med. Chem. (1997) [Pubmed]
  11. Synthesis and biological evaluation on hMC3, hMC4 and hMC5 receptors of gamma-MSH analogs substituted with L-alanine. Grieco, P., Balse-Srinivasan, P., Han, G., Weinberg, D., MacNeil, T., Van der Ploeg, L.H., Hruby, V.J. J. Pept. Res. (2002) [Pubmed]
  12. Melanocortins and cardiovascular regulation. Versteeg, D.H., Van Bergen, P., Adan, R.A., De Wildt, D.J. Eur. J. Pharmacol. (1998) [Pubmed]
  13. Structure activity studies of the melanocortin antagonist SHU9119 modified at the 6, 7, 8, and 9 positions. Haskell-Luevano, C., Lim, S., Yuan, W., Cone, R.D., Hruby, V.J. Peptides (2000) [Pubmed]
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