Nature 299, 555 - 557 (07 October 1982); doi:10.1038/299555a0

Potent new inhibitors of human renin

M. Szelke, B. Leckie^*, A. Hallett, D. M. Jones, J. Sueiras, B. Atrash & A. F. Lever^*

Department of Chemical Pathology, Royal Postgraduate Medical School, London W12 0HS, UK
^*MRC Blood Pressure Unit, Western Infirmary, Glasgow G11 6NT, UK

The renal acid protease renin selectively cleaves its plasma substrate angiotensinogen to release the decapeptide angiotensin I, which in turn is cleaved by a carboxydipeptidase converting enzyme to yield the pressor octapeptide angiotensin II¹. It is generally accepted that the renin−angiotensin system has a physiological role in blood pressure and electrolyte homeostasis², and that abnormalities of the system contribute to certain forms of hypertension³. We previously showed that reduction of the Leu¹⁰−Leu¹¹ scissile peptide bond in the (6−13) octapeptide sequence 2 of equine angiotensinogen produced potent and selective inhibitors of canine plasma renin⁵. We have now used the same approach to modify the recently elucidated N-terminal sequence⁶ of human angiotensinogen and report here the production of highly active and species-specific in vitro inhibitors of endogenous human renin cleaving renin substrate in human plasma. Whereas the (6−13) octapeptide H-112 of human angiotensinogen is only a weak inhibitor of human plasma renin (IC₅₀ = 313 µM), the analogue H-113, in which the scissile Leu−Val bond has been reduced, has IC₅₀ = 0.19 µM. Extension of H-113 with Pro at the N-terminus and with Lys at the C-terminus⁷, giving the decapeptide derivative H-142, increases inhibitory potency further (IC₅₀ = 10 nM). We believe that the high in vitro inhibitory potencies of H-113 and H-142 are due to the ability of the reduced moiety —CH₂—NH— to act as a non-hydrolysable analogue of the tetrahedral transition state formed during hydrolysis of the (10−11) peptide bond. H-113 and H-142 are strongly species specific, and are highly specific for renin among acid proteases: H-142 has no inhibitory effect in vitro on human cathepsin D or renal acid protease at a concentration of 712 µM.

References

1.	Skeggs, L. T., Dorer, F. E., Levine, M., Lentz, K. E. & Kahn, J. R. in The Renin-Angiotensin System (eds Johnson, J. A. & Anderson, R. R.) 1−27 (Plenum, New York, 1980).
2.	MacGregor, G. A., Markandu, N. D., Roulston, J. E., Jones, J. C. & Morton, J. J. Nature 291, 329−331 (1981). | PubMed | ISI | ChemPort |
3.	Atkinson, A. B. et al. in The Therapeutics of Hypertension, 29−61 (Academic Press and The Royal Society of Medicine, London, 1980).
4.	Parry, M. J., Russell, A. B. & Szelke, M. in Chemistry and Biology of Peptides (ed. Meienhofer, J.) 541−544 (Ann Arbor Science, Ann Arbor, 1972). | ChemPort |
5.	Szelke, M. et al. Hypertension 4, Suppl. II, 59−69 (1982). | PubMed | ISI | ChemPort |
6.	Tewksbury, D. A., Dart, R. A. & Travis, J. Biochem. biophys. Res. Commun. 99, 1311−1315 (1981). | PubMed | ISI | ChemPort |
7.	Burton, J., Cody, R. J., Herd, J. A. & Haber, E. Proc. natn. Acad. Sci. U.S.A. 77, 5476−5479 (1980). | ChemPort |
8.	Skeggs, L. T., Kahn, J. R., Lentz, K. & Shumway, N. P. J. exp. Med. 106, 439−453 (1957). | Article | PubMed | ISI | ChemPort |
9.	Skeggs, L. T., Lentz, K. E., Hochstrasser, H. & Kahn, J. R. Can. med. Ass. J. 90, 185−189 (1964); J. exp. Med. 128, 13−34 (1968). | Article | PubMed | ISI | ChemPort |
10.	Kokubu, T. et al. Nature 217, 456−457 (1968). | PubMed | ISI | ChemPort |
11.	Kokubu, T. et al. Biochem. Pharmac. 22, 3217−3223 (1973). | Article | ISI | ChemPort |
12.	Poulsen, K., Burton, J. & Haber, E. Biochemistry 12, 3877−3882 (1973). | PubMed | ISI | ChemPort |
13.	Burton, J., Poulsen, K. & Haber, E. Biochemistry 14, 3892−3898 (1975). | PubMed | ISI | ChemPort |
14.	Haber, E. & Burton, J. Fedn Proc. 38, 2768−2773 (1979). | ChemPort |
15.	Quinn, T. & Burton, J. in Peptides (eds Rich, D. H. & Gross, E.) 443−445 (Pierce Chemical Company, Rockford, 1981). | ChemPort |
16.	Lienhard, G. E. Science 180, 149−154 (1973). | PubMed | ISI | ChemPort |
17.	Hille, M. B., Barrett, A. J., Dingle, J. T. & Fell, H. B. Expl Cell. Res. 61, 470 (1970). | ChemPort |
18.	Barany, G. & Merrifield, R. B. in The Peptides (eds Gross, E. & Meienhofer, J.) 1−284 (Academic, New York, 1980). | ChemPort |
19.	Chillemi, N. & Merrifield, R. B. Biochemistry 8, 4344−4346 (1969). | PubMed | ISI |
20.	Brown, T. & Jones, J. H. J. chem. Soc. chem. Commun. 648 (1981). | Article | ChemPort |
21.	Yamashiro, D. & Li, C. H. J. Am. chem. Soc. 95, 1310−1315 (1973). | PubMed | ISI | ChemPort |
22.	Erickson, B. W. & Merrifield, R. B. J. Am. chem. Soc. 95, 3757−3763 (1973). | PubMed | ISI | ChemPort |
23.	Felix, A. M. & Jimenez, M. H. Analyt. Biochem. 52, 377−381 (1973). | PubMed | ISI | ChemPort |
24.	König, W. & Geiger, R. Chem. Ber. 103, 788−798 (1970). | PubMed | ISI | ChemPort |
25.	Szelke, M. et al. in Molecular Endocrinology (eds MacIntyre, I. & Szelke, M.) 57−70 (Elsevier, Amsterdam, 1977). | ChemPort |
26.	Ito, A., Takahashi, R. & Baba, Y. Chem. Pharm. Bull. 23, 3081−3087 (1975). | ISI | ChemPort |
27.	Szelke, M., Hallett, A. & Jones, D. M. European Patent Application 0-045-665 (February 1982).
28.	Millar, J. A., Leckie, B. J., Morton, J. J., Jordan, J. & Tree, M. Clinica chim. Acta 101, 5−15 (1980). | Article | ISI | ChemPort |
29.	Poulsen, K. & Jörgensen, J. J. clin. Endocr. Metab. 39, 816−815 (1974). | PubMed | ISI | ChemPort |
30.	Hackenthal, E., Hackenthal, R. & Hilgenfeldt, U. Biochim. biophys. Acta 522, 574−588 (1978). | Article | PubMed | ISI | ChemPort |