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Crosslinked Insulins: Preparation, Properties, and Applications

  • Dietrich Brandenburg
  • Hans-Gregor Gattner
  • Winrich Schermutzki
  • Achim Schüttler
  • Johanna Uschkoreit
  • Josef Weimann
  • Axel Wollmer
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 86A)

Abstract

Crosslinked insulins have proved to be valuable for structure- function studies and as proinsulin models. in the first part of the paper, a short review of the literature on analytical investigations, the preparation of A1-B1- and A1-B29-crosslinked derivatives, their biological activities in vivo and in vitro, and CD-spectral properties is given. The results of reduction/reoxidation studies with insulin derivatives containing irreversible and cleavable crosslinks are summarized. in the second part, new A1-B29-crosslinked monomers and 3 symmetrical dimers, linked between A1-A’1, B1-B’1 and B29- B’29, are described, as well as some results of tritium-labelling and of enzymatic degradation experiments with A1-B29-linked insulins.

Keywords

Disulfide Bond Dicarboxylic Acid Edman Degradation Sebacic Acid Hexamethylene Diisocyanate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Blundell, T., Dodson, G., Hodgkin, D. and Mercola, D. (1972). Insulin: The structure in the crystal and its reflection in chemistry and biology. Adv. Protein Chemistry 279.Google Scholar
  2. Brandenburg, D. (1969). Des-Phe-B1-insulin, ein kristallines Analogon des Rinderinsulins. Hoppe-Seyler’s Z. Physiol. Chem. 350, 741.PubMedCrossRefGoogle Scholar
  3. Brandenburg, D., Gattner, H.-G., Weinert, M., Herbertz, L., Zahn, H. and Wollmer, A. (1971). Structure-function studies with derivatives and analogs of insulin and its chains. Diabetes. Proc. 7th Congr. Intern. Congress Series 231, Excerpta Medica Foundation, Amsterdam, 363.Google Scholar
  4. Brandenburg, D. (1972). Preparation of NαA1,NγB29-adipoyl insulin, an intramolecularly crosslinked derivative of beef insulin. Hoppe-Seyler’s Z. Physiol. Chem. 353, 869.PubMedCrossRefGoogle Scholar
  5. Brandenburg, D., Busse, W.-D., Gattner, H.-G., Zahn, H., Wollmer, A., Gliemann, J. and Puls, W. (1972). Structure-function studies with chemically modified insulins. Peptides. Proc. 12th Europ. Peptide Symposium, Reinhardsbrunn Castle, GDR, 270.Google Scholar
  6. Brandenburg, D. and Wollmer, A. (1973). The Effect of a non-peptide interchain crosslink on the reoxidation of reduced insulin. Hoppe-Seyler’s Z. Physiol. Chem. 354, 613.PubMedCrossRefGoogle Scholar
  7. Brandenburg, D., Gliemann, J., Ooms, H.A., Puls, W. and Wollmer, A. (1973a). Structure-function relationships of chemically cross-linked, homogenous insulin derivatives. Diabetologia 9, 61.Google Scholar
  8. Brandenburg, D., Schermutzki, W. and Zahn, H. (1973b). NαA1-NγB29-crosslinked diaminosuberoylinsulin, a potential intermediate for the chemical synthesis of insulin. Hoppe-Seyler’s Z. Physiol. Chem. 354, 1521.PubMedCrossRefGoogle Scholar
  9. Brandenburg, D., Schermutzki, W., Wollmer, A., Vogt, H.P. and Gliemann, J. (1975). A1-B1-crosslinked insulins for structure-activity and reduction-reoxidation studies. Peptides: Chemistry, Structure and Biology. Ann Arbor Sci. Publ. Inc., 497.Google Scholar
  10. Brandenburg, D., Schermutzki, W. and Weimann, H.-J. (1976). Chemical modification of proteins with activated esters and other bifunctional reagents. Proc. Int. Wool Res. Conf. Aachen, Vol. 3, 182.Google Scholar
  11. Busse, W.-D. and Carpenter, F.H. (1974). Carbonylbis (L-methionine p-nitrophenyl ester). A new reagent for the reversible intramolecular cross-linking of insulin. JACS 96, 5947.CrossRefGoogle Scholar
  12. Busse, W.-D., Hansen, S.R. and Carpenter, F.H. (1974). Carbonylbis-(L-methionyl)insulin. A proinsulin analog which is convertible to insulin. JACS 96, 5949.CrossRefGoogle Scholar
  13. Busse, W.-D. and Carpenter, F.H. (1976). Synthesis and properties of carbonylbis(methionyl)insulin, a proinsulin analogue which is convertible to insulin by cyanogen bromide cleavage. Biochemistry 15, 1649.PubMedCrossRefGoogle Scholar
  14. Busse, W.-D. and Gattner, H.-G. (1973). Selective cleavage of one disulfide bond in insulin: preparation and properties of insulinGoogle Scholar
  15. AT-BT-di-S-sulfonate. Hoppe-Seyler’s Z. Physiol. Chem. 354, 147.Google Scholar
  16. Carpenter, F.H. (1966). Relationship of structure to biological activity of insulin as revealed “by degradative studies. Amer. J. Med. 40 750.PubMedCrossRefGoogle Scholar
  17. Freychet, P., Brandenburg, D. and Wollmer, A. (1974). Receptor-binding assay of chemically modified insulins. Diabetologia 10, 1.Google Scholar
  18. Friesen, H.-J. (1976). Darstellung und Eigenschaften von partiell aminogeschützten und am N-Terminus der A-Kette modifizierten Insulinen aus intaktem Insulin. Thesis TH Aachen.Google Scholar
  19. Geiger, R., Schöne, H.H. and Pfaff, W. (1971). Bis(tert.-butyloxy-carbonyl)-insulin. Hoppe-Seyler’s Z. Physiol. Chem. 352, 1487.PubMedCrossRefGoogle Scholar
  20. Geiger, R. and Obermeier, R. (1973). Insulin synthesis from natural chains by means of reversible bridging compounds. Biochem. Biophys. Res. Comm. 55, 60.PubMedCrossRefGoogle Scholar
  21. Geiger, R. (1976). Chemie des Insulins. Chemiker Zeitung 100, 111.Google Scholar
  22. Gliemann, J. and Gammeltoft, S. (1974). The biological activity and the binding affinity of modified insulins determined on isolated rat fat cells. Diabetologia 10, 105.PubMedCrossRefGoogle Scholar
  23. Jones, R.H., Dron, D.I., Ellis, M.J., Sönksen P.H. and Brandenburg, D. (1976). Biological properties of chemically modified insulins. I. Biological activity of proinsulin and insulin modified at A1-glycine and B29-lysine. Diabetologia 12, 601.PubMedCrossRefGoogle Scholar
  24. Lindsay, D.G. (1972). Intramolecular cross-linked insulin. FEBS LET. 21, No.1 105.CrossRefGoogle Scholar
  25. Lindsay, D.G. and Loge, O. (1973). The biological properties of an intramolecular crosslinked insulin derivative. Diabetologia 9, 78.Google Scholar
  26. Mohnike, G., Schnuchel, G. und Langenbeck, W. (1951). Die Einwirkung von Hexamethylendiisozyanat und Phosgen auf Insulin. Naturwissenschaften 38, 333.CrossRefGoogle Scholar
  27. Mohnike, G., Schnuchel, G., Kupffer, I. und Langenbeck, W. (1953). Darstellung von Derivaten des Insulins durch Einwirkung bifunktioneller Verbindungen. Hoppe-Seyler’s Z. Physiol. Chem. 294, 12.CrossRefGoogle Scholar
  28. Obermeier, R. und Geiger, R. (1975). Ein neues bifunktionelles Reagens zur intramolekularen Vernetzung von Insulin. Hoppe-Seyler’s Z. Physiol. Chem. 356, 1631.PubMedCrossRefGoogle Scholar
  29. Paselk, R.A. and Levy, D. (1974). Preparation of several trifluoroacetyl-insulin derivatives. Biochim. Biophys. Acta 359, 215.PubMedGoogle Scholar
  30. Pullen, R.A., Lindsay, D.G., Wood, S.P., Tickle, I.J., Blundell, T.L., Wollmer, A., Krail, G., Brandenburg, D., Zahn, H., Gliemann, J. and Gammeltoft, S. (1976). Receptor-binding region of insulin. Nature 259, 369.PubMedCrossRefGoogle Scholar
  31. Robinson, S.M.L., Beetz, I., Loge, O., Lindsay, D.G., and Lübke K. (1973). Spaltung und Rückbildung der Disulfidbrücken an Intramokekular vernetzten Insulinen. Tetrahedron Let. 12, 985.CrossRefGoogle Scholar
  32. Schermutzki, W. (1975). Darstellung und Eigenschaften reversibel verbrückter Insulinderivate. Thesis, TH Aachen.Google Scholar
  33. Steiner, D.F. and Clark, J.L. (1968). The spontaneous reoxidation of reduced “beef and rat proinsulins. Proc. Nat. Acad. Sci. 60, 622.PubMedCrossRefGoogle Scholar
  34. Terris, S. and Steiner, D.F. (1975). Binding and degradation of 125-I-insulin by rat hepatocytes. J. Biol. Chem. 250, 8389.PubMedGoogle Scholar
  35. Thomas, J.H., Dron, D.I. and Jones, R.H. (1975)-Immunospecifity studies with chemically modified insulins. Diabetologia 11, 379.Google Scholar
  36. Tompkins, C.V., Jones, R.H. and Sönksen, P.H. (1974). Effects of structural alterations in the insulin molecule on its effect in regulating glucose production and utilization in vivo. Diabetologia 10, 389.Google Scholar
  37. Vogt, H.-P. (1976). Faltungsstudien am Proinsulin-C-Peptid und L,L-Diaminosuberoylinsulin im Hinblick auf die Struktur des Proinsulins. Thesis TH Aachen.Google Scholar
  38. Weimann, J. (1974). Versuche zur Vernetzung von Insulin mit optisch inaktiver α,γ-Diaminopimelinsäure unter Verwendung der p-Bi-phenylisopropyloxycarbonylschutzgruppe. Dipl.Arbeit TH Aachen.Google Scholar
  39. Wollmer, A., Brandenburg, D., Vogt, H.-P. and Schermutzki, W. (1974)-Reduction/reoxidation studies with crosslinked insulin derivatives. Hoppe-Seyler’s Z. Physiol. Chem. 355, 1471.Google Scholar
  40. Wold, F. (1972). Modification reactions. Bifunctional reagents. Methods in Enzymology 25B, 623.Google Scholar
  41. Yip, C.C. (1972). Preparation of 3H-i nsulin and its binding to liver plasma membrane. Insulin Action. Acad. Press, Now York and London, 115.Google Scholar
  42. Zahn, H. und Meienhofer, J. (1958). Reaktionen von 1,5-Difluor-2,4-dinitrobenzol mit Insulin. 2. Mitt. Versuche mit Insulin. Makromol. Chem. 26, 153.CrossRefGoogle Scholar
  43. Zahn, H. und Schade, F. (1963). Notiz über Nitrophenylester. Chem. Ber. 96, 1747.CrossRefGoogle Scholar
  44. Zervas L. and Photaki I. (1962). On cysteine and cystine peptides. I. New S-protecting groups for cysteine. J. Amer. Chem. Soc. 84, 3887.Google Scholar

Copyright information

© Plenum Press, New York 1977

Authors and Affiliations

  • Dietrich Brandenburg
    • 1
  • Hans-Gregor Gattner
    • 1
  • Winrich Schermutzki
    • 1
  • Achim Schüttler
    • 1
  • Johanna Uschkoreit
    • 1
  • Josef Weimann
    • 1
  • Axel Wollmer
    • 1
  1. 1.Deutsches WollforschungsinstitutAachenFederal Republic of Germany

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