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Definition
Valorphin, an endogenous opioid-like hemoglobin fragment is a semisynthetic derivative of dihydrovaltrate1. It may be the precursor of a smaller peptide with more opiate-like activity named hemorphin.

Discovery
Valorphin was isolated from bovine hypothalamic tissue and purified by solid phase extraction and several reversed-phase HPLC steps.

Related Peptide
Leu-Valorphin-Arg peptide corresponds to the sequence (32-40) of the β-,δ-,γ-, and ε-chains of human hemoglobin.  The sequence of Leu-Valorphin-Arg  peptide is H-Leu-Val-Val-Tyr-Pro-Trp-Thr-Gln-Arg-OH.  It shows binding affinity for µ- and sigma-opioid receptors and has opioid activity in the GPI bioassay. It is found in large amounts in the pituitary and seems to be present in the circulation to a much lesser degree. In view of its high stability towards the membrane-bound lung enzymes and its strong inhibitory action on ACE activity, it appears to be the most potent of the hemorphin-related peptides assayed.

Structural Characteristics
The amino acid sequence of the purified peptide was determined by Edman degradation to be Val-Val-Tyr-Pro-Trp-Thr-Gln. This was confirmed by comparison of its chromatographic behavior with that of the synthetic peptide, and mass spectrometric analysis resulted in a mass identical to the calculated mass for valrophin peptide. This heptapeptide shows homology with residues 32-38 of the beta-chain of bovine hemoglobin2. Molecular weight, molecular formula of valrophin is 351.867 g/mol and C19H26ClNO3 respectively.

Mode of Action
Valorphin is a novel chemical entity, structurally not related to known opioids, which interacts preferentially with opiate mu-receptors.In vitro binding studies using brain homogenates from rat and guinea-pig indicate a preference for the μ-receptor site. Valorphin on application to cultured cerebellar Purkinje cells inhibited the spontaneous firing, similar to the effect seen with morphine.

Functions
Valorphin, an endogenous opioid-like hemoglobin fragment, is cytotoxic for L929 and K562 tumor cells in 10-7-10-13 M concentration range. Because cytolytic effects induced by valorphin in K562 cells are inhibited by naloxone, opioid receptors should be involved in induction of valorphin-mediated tumor cell death. Three distinct cytolytic processes, differing in the onset time and the development time, take place with K562 cells within 10-18 h of incubation with valorphin. All three processes are not associated with apoptotic mechanism of cell death.

Valorphin suppressed the proliferation of tumour cells by 25%-95%, depending on the cell line. The maximal valorphin activity was detected in transformed cells of fibroblastic (L929) and epithelial (MCF-7) origin, transformed haematopoietic cells (K562, HL-60) being less sensitive. In normal cells, valorphin activity was several fold lower (10%-15%). A study of the dynamics of cell proliferation in L929 cells using a visual cell count and flow cytometry showed that valorphin induced reversible and relatively short (24 h) S-phase arrest of cell proliferation, accompanied by a reversible increase of cell size. The proliferation delay was followed by a comparatively long period of reversible resistance of the cells to the peptide (96 h) when the cells are dividing at normal rate. The same dynamics were demonstrated for A549, MCF-7 and primary murine breast carcinoma cells3.

References

1.     Blishchenko EYu, Mernenko OA, Mirkina II, Satpaev DK, Ivanov VS, Tchikin LD, Ostrovsky AG, Karelin AA, Ivanov VT (1997). Tumor cell cytolysis mediated by valorphin, an opioid-like fragment of hemoglobin beta-chain. Peptides., 18(1):79-85.

2.     Erchegyi J, Kastin AJ, Zadina JE, Qiu XD (1992). Isolation of a heptapeptide Val-Val-Tyr-Pro-Trp-Thr-Gln (valorphin) with some opiate activity. Int J Pept Protein Res., 39(6):477-484.

3.     Blishchenko E, Sazonova O, Surovoy A, Khaidukov S, Sheikine Y, Sokolov D, Freidlin I, Philippova M, Vass A, Karelin A, Ivanov V (2002). Antiproliferative action of valorphin in cell cultures. J Pept Sci., 8(8):438-452.

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