Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1990-05-23
1994-10-25
Yarbrough, Amelia Burgess
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
435 6, C07H 2104
Patent
active
053590457
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a nucleic acid coding for the human angiotensin converting enzyme (ACE) as well as vectors containing this nucleic acid and the utilization of these latter for the production of human ACE. The invention also relates to the uses of this nucleic acid, especially in the area concerned with the design of new inhibitors of human ACE.
The ACE, or peptidyl dipeptidase A (EC 3.4.15.1), or also kininase II, plays an important role in the regulation of arterial blood pressure, by hydrolysing angiotensin I (inactive peptide released after cleavage of angiotensinogen by renin) to angiotensin II, a vasopressor agent playing a role in the mechanisms of arterial hypertension (SKEGGS, L.T., et al (1986) J. Exp. Med., 103, 295-299).
The inhibition of the activity of the ACE by EDTA and metal chelators indicates that it is a metallopeptidase, more particularly a zinc peptidase capable of hydrolysing not only angiotension I but also bradykinin (a vasodilator and natriuretic peptide which it transforms into an inactive heptapeptide), and many other peptides with biological activity (YANG, H.Y.T. et al (1970) Biochim. Biophys. Acta, 214, 374-376; ERDOS, E.G., et al (1987) Lab. Invest., 56, 345-348).
The ACE is a peptidase widely distributed in the organism, which is found, for example, in the form of a membrane enzyme at the surface of the vascular endothelial cells and renal epithelial cells, as well as in the form of an enzyme circulating in the plasma (ERDOS et al (1987) cited above; CARDWELL, P.R.B. et al (1976) Science, 191, 1050-1051; RYAN, U.S. et al (1976) Tissue Cell, 8, 125-145).
Methods for the purification of human or animal ACE have already been described (in particular in BULL H.G. et al (1985), J. Biol. Chem., 260, 2963-2972; HOOPER, N.M. et al (1987), Biochem. J. 247, 85-93).
However, the structure of the human ACE is not known at present. Only some peptide sequences of the ACE of animal origin have been published (BERNSTEIN, K.E. et al (1988), Kidney Int., 33, 652-655; HARRIS, R.B. et al (1985), J. Biol. Chem., 260, 2208-2211; IWATA, K. et al (1982) Biochem. Biophys. Res. Commun., 107, 1097-1103; IWATA, K. et al (1983) Arch. Biochem. Biophys., 227, 188-201; ST CLAIR, D.K. et al (1986) Biochem. Biophys. Res. Commun., 141, 968-972; SOFFER, R.L. et al (1987) Chin. Exp. Hyp. A9, 229-234).
Some attempts to clone the DNA coding for the animal ACE have been carried out starting from two organs rich in ACE, the kidneys and the lungs, but no complete nucleic acid coding for the animal ACE has, however, been described; only several fragments of such a nucleic acid have been described (DELUCA-FLAHERTY, C. et al (1987) Int. J. Peptide Protein Res., 29, 678-684; BERNSTEIN K. E. et al, (1988, J. Biol. Chem., 263, 11021-11024)). The quantities of messenger RNA (mRNA) coding for the ACE are probably too small in these organs to make possible the cloning of a complementary DNA (cDNA) of this mRNA. No attempt to clone the DNA coding for the human ACE has been described up to now.
Although the physiological role of the ACE in the extra-vascular tissues is still unknown, it is henceforth well established that this enzyme, which is found in the vascular endothelium and in the plasma, plays an essential role in the homeostasis of the circulation by its action of cleaving the carboxy-terminal dipeptide of angiotensin I, thus activating this latter by converting it into angiotensin II which is a vasoconstrictor peptide, which stimulates the production of aldosterone and facilitates adrenergic transmission.
In view of the essential role of angiotensin II in the control of arterial blood pressure, active research into the synthesis of inhibitors of the ACE has grown. Captopril was the first oral inhibitor of the ACE, followed by many other compounds. At present, the inhibitors of the ACE occupy an important place in the treatment of arterial hypertension. Since the complete structure of the ACE is not known, the above-mentioned inhibitors were designed on the basis of the structure of zinc proteases possessing
REFERENCES:
patent: 4358535 (1982-11-01), Falkow et al.
K. E. Bernstein et al, "The isolation of angiotensin-converting enzyme cDNA" The Journal of Biological Chemistry, 263, No. 23, Aug. 15, 1988, pp. 11021-11024.
H. G. Bull et al, "Purification of angiotensin-coverting enzyme from rabbit lung and human plasma by affinity chromatography" The Journal of Biological Chemistry, 260, No. 5, Mar. 10, 1985, pp. 2963-2972.
T. Kreofsky et al, "Purification of human lung antiotensin converting enzyme (ACE) and production of anti-catalytic monoclonal antibodies MoAb" Federation Proceeings (US), 45, (6) (1986).
R. K. A. Allen et al, "Monoclonal antibodies to human pulmonary angiotensin-converting enzyme" Australian and New Zealand Journal of Medicine, Suppl. 2, 18, (3): 547 (1988).
Iwata et al, JP-A-61 186 399 (Fuji Pharmaceutical), Chemical Abstracts, 106, p. 470, No. 16946f (1987).
Danilov et al, Biotechnol. Appl. Biochem. 9: 319-322 (1987), Chemical Abstracts, 108, p. 266, No. 18303j (1988).
Hiroshi et al, Jpn. Circ. J. 49: 1175-1179 (1985), Chemical Abstracts, 104, p. 7, No. 179632y, (1986).
Deluca-Flaherty et al, Int. J. Pept. Protein Res. 29: 678-684 (1987) (cited on p. 2 of this application), Chemical Abstracts, 107, p. 169, No. 148356u (1987).
Bernstein et al, Laboratory Investigation (US) 60 (1): 9A (1989).
Alhenc-Gelas Francois
Corvol Pierre
Hubert Christine
Soubrier Florent
Burgess Yarbrough Amelia
Institut National de la Sante et de la Recherche Medicale
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