Skip to main content
SpringerLink
Log in

Stability of Protein Pharmaceuticals

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Recombinant DNA technology has now made it possible to produce proteins for pharmaceutical applications. Consequently, proteins produced via biotechnology now comprise a significant portion of the drugs currently under development. Isolation, purification, formulation, and delivery of proteins represent significant challenges to pharmaceutical scientists, as proteins possess unique chemical and physical properties. These properties pose difficult stability problems. A summary of both chemical and physical decomposition pathways for proteins is given. Chemical instability can include proteolysis, deamidation, oxidation, racemization, and β-elimination. Physical instability refers to processes such as aggregation, precipitation, denaturation, and adsorption to surfaces. Current methodology to stabilize proteins is presented, including additives, excipients, chemical modification, and the use of site-directed mutagenesis to produce a more stable protein species.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. D. Blohm, C. Bollschweiler, and H. Hillen. Angew. Chem. Int. Ed. Engl. 27:207–225 (1988).

    Google Scholar 

  2. L. P. Gage. Am. J. Pharm. Ed. 50:368–370 (1986).

    Google Scholar 

  3. H. H. Tallan and W. H. Stein. J. Biol. Chem. 200:507–514 (1953).

    Google Scholar 

  4. U. J. Lewis and E. V. Cheever. J. Biol. Chem. 240:247–252 (1965).

    Google Scholar 

  5. U. J. Lewis, E. V. Cheever, and W. C. Hopkins. Biochim. Biophys. Acta 214:498–508 (1970).

    Google Scholar 

  6. G. W. Becker, P. M. Tackitt, W. W. Bromer, D. S. Lefeber, and R. M. Riggin. Biotech. Appl. Biochem. 10:326–337 (1988).

    Google Scholar 

  7. S. A. Berson and R. S. Yalow. Diabetes 15:875–879 (1966).

    Google Scholar 

  8. B. V. Fisher and P. B. Porter. J. Pharm. Pharmacol. 33:203–206 (1981).

    Google Scholar 

  9. F. S. M. Van Kleef, W. W. de Jong, and H. J. Hoenders. Nature 258:264–266 (1975).

    Google Scholar 

  10. T. Flatmark and K. Sletten. J. Biol. Chem. 243:1623–1629 (1968).

    Google Scholar 

  11. J. O. Minta and R. H. Painter. Immunochemistry 9:821–832 (1972).

    Google Scholar 

  12. R. P. Diaugustine, B. W. Gibson, W. Aberth, M. Kelly, C. M. Ferrua, Y. Tomooka, C. F. Brown, and M. Walker. Anal. Biochem. 165:420–429 (1987).

    Google Scholar 

  13. M. F. Perutz and J. H. Fogg. J. Mol. Biol. 138:669–670 (1980).

    Google Scholar 

  14. K. U. Yuksel and R. W. Gracy. Arch. Biochem. Biophys. 248:452–459 (1986).

    Google Scholar 

  15. P. M. Yuan, J. M. Talent, and R. W. Gray. Mech. Age. Dev. 17:151–162 (1981).

    Google Scholar 

  16. H. Maeda and K. Kuromizu. J. Biochem. (Tokyo) 81:25–35 (1977).

    Google Scholar 

  17. L. Graf, G. Cseh, I. Nagy, and M. Kurcz. Acta Biochim. Biophys. Acad. Sci. Hung. 5:299–303 (1970).

    Google Scholar 

  18. T. J. McDonald, H. Jornvall, K. Tatemoto, and V. Mutt. FEBS Lett. 156:349–356 (1983).

    Google Scholar 

  19. L. Graf, S. Bajusz, A. Patthy, E. Barat, and G. Cseh. Acta Biochim. Biophys. Acad. Sci. Hung. 6:415–418 (1971).

    Google Scholar 

  20. N. P. Bhatt, K. Patel, and R. T. Borchardt. Pharm. Res. 5:S72 (1988).

    Google Scholar 

  21. A. B. Robinson and C. J. Rudd. In B. L. Horecker and E. R. Stadtman (eds.), Current Topics in Cellular Regulations, Vol. 8, Academic Press, New York, 1974, pp. 247–295.

    Google Scholar 

  22. E. Sondheimer and R. W. Holley. J. Am. Chem. Soc. 76:2467–2470 (1954).

    Google Scholar 

  23. E. E. Haley, B. J. Coreoran, F. E. Dorer, and D. L. Buchanan. Biochemistry 5:3229–3235 (1966).

    Google Scholar 

  24. A. R. Battersby and J. C. Robinson. J. Chem. Soc. 259–269 (1955).

  25. P. Bornstein and G. Balian. Methods. Enzymol. 47:132–145 (1977).

    Google Scholar 

  26. T. Geiger and S. Clarke. J. Biol. Chem. 262:785–794 (1987).

    Google Scholar 

  27. Y. C. Meinwald, E. R. Stimson, and H. A. Scheraga. Int. J. Peptide Protein Res. 28:79–84 (1986).

    Google Scholar 

  28. D. W. Aswad. J. Biol. Chem. 259:10714–10721 (1984).

    Google Scholar 

  29. B. A. Johnson and D. W. Aswad. Biochemistry 24:2581–2586 (1985).

    Google Scholar 

  30. P. Bornstein. Biochemistry 9:2408–2421 (1970).

    Google Scholar 

  31. A. Di Donato, P. Galletti, and G. D'Alessio. Biochemistry 25:8361–8368 (1986).

    Google Scholar 

  32. P. Galletti, A. Ciardiello, D. Ingrosso, A. Di Donato, and G. D'Alessio. Biochemistry 27:1752–1757 (1988).

    Google Scholar 

  33. S. Lou, C. Liao, J. F. McClelland, and D. J. Graves. Int. J. Peptide Protein Res. 29:728–733 (1987).

    Google Scholar 

  34. K. Patel and R. T. Borchardt. Pharm. Res. 5:S72 (1988).

    Google Scholar 

  35. K. Patel, C. Oliyai, R. T. Borchardt, and M. C. Manning. J. Cell. Biochem. 13A:88 (1989).

    Google Scholar 

  36. S. A. Bernhard, A. Berger, H. J. Carter, E. Katchalski, M. Sela, and Y. Shalitin. J. Am. Chem. Soc. 84:2421–2434 (1962).

    Google Scholar 

  37. Y. Shalitin and S. A. Bernhard. J. Am. Chem. Soc. 88:4711–4721 (1966).

    Google Scholar 

  38. M. A. Ondetti, A. Deer, J. T. Sheeham, J. Pluscec, and O. Kocy. Biochemistry 7:4069–4075 (1968).

    Google Scholar 

  39. M. Bodanszky and J. Z. Kwei. Int. J. Peptide Protein Res. 12:69–74 (1978).

    Google Scholar 

  40. S. A. Bernhard. Ann. N.Y. Acad. Sci. 421:28–40 (1983).

    Google Scholar 

  41. J. K. Blodgett, G. M. Loudon, and K. D. Collins. J. Am. Chem. Soc. 107:4305–4313 (1985).

    Google Scholar 

  42. S. Capasso, C. A. Mattia, L. Mazzarella, and A. Zagari. Int. J. Peptide Protein Res. 23:248–255 (1984).

    Google Scholar 

  43. A. J. Alder, G. D. Fasman, and E. R. Blout. J. Am. Chem. Soc. 85:90–97 (1963).

    Google Scholar 

  44. G. Perseo, R. Furino, M. Galantino, B. Gioia, V. Malatesta, and R. D. Castiglione. Int. J. Peptide Protein Res. 27:51–60 (1986).

    Google Scholar 

  45. M. Bodanszky and S. Natarajan. J. Org. Chem. 40:2495–2499 (1975).

    Google Scholar 

  46. A. B. Robinson, J. W. Scotchler, and J. H. McKerow. J. Am. Chem. Soc. 95:8156–8159 (1973).

    Google Scholar 

  47. J. W. Scotchler and A. B. Robinson. Anal. Biochem. 59:319–322 (1974).

    Google Scholar 

  48. A. B. Robinson, J. H. McKerrow, and P. Cary. Proc. Natl. Acad. Sci. USA 66:753–757 (1970).

    Google Scholar 

  49. A. B. Robinson, J. H. McKerrow, and M. Legaz. Int. J. Peptide Protein Res. 6:31–35 (1974).

    Google Scholar 

  50. T. Flatmark. Acta Chem. Scand. 20:1487–1496 (1966).

    Google Scholar 

  51. S. Clarke. Int. J. Peptide Protein Res. 30:808–821 (1987).

    Google Scholar 

  52. P. Bornstein and G. Balian. J. Biol. Chem. 245:4854–4856 (1970).

    Google Scholar 

  53. A. A. Kossiakoff. Science 240:191–194 (1988).

    Google Scholar 

  54. R. Lura and V. Schirch. Biochemistry 27:7671–7677 (1988).

    Google Scholar 

  55. M. Bodanszky, J. C. Tolle, S. S. Deshmane, and A. Bodanszky. Int. J. Peptide Protein Res. 12:57–68 (1978).

    Google Scholar 

  56. B. N. Manjula, A. S. Achary, and P. J. Vithayathil. Int. J. Peptide Protein Res. 8:275–282 (1976).

    Google Scholar 

  57. S. Charache, J. Fox, P. McCurdy, H. Kazazian, Jr., and R. Winslow. J. Clin. Invest. 59:652–658 (1977).

    Google Scholar 

  58. U. J. Lewis, R. N. P. Singh, L. F. Bonewald, and B. K. Seavey. J. Biol. Chem. 256:11645–11650 (1981).

    Google Scholar 

  59. T. J. Ahern and A. M. Klibanov. Science 228:1280–1284 (1985).

    Google Scholar 

  60. S. E. Zale and A. M. Klibanov. Biochemistry 25:5432–5444 (1986).

    Google Scholar 

  61. C. F. Midelfort and A. H. Mehler. Proc. Natl. Acad. Sci. USA 69:1816–1819 (1972).

    Google Scholar 

  62. L. Graf, G. Hajos, A. Patthy, and G. Cseh. Horm. Metab. Res. 5:142–143 (1973).

    Google Scholar 

  63. Y. P. Venkatesh and P. J. Vithayathil. Int. J. Peptide Protein Res. 25:27–32 (1985).

    Google Scholar 

  64. Y. P. Venkatesh and P. J. Vithayathil. Int. J. Peptide Protein Res. 23:494–505 (1984).

    Google Scholar 

  65. G. R. Marshall and R. B. Merrifield. Biochemistry 4:2394–2401 (1965).

    Google Scholar 

  66. C. C. Yang and R. B. Merrifield. J. Org. Chem. 41:1032–1041 (1976).

    Google Scholar 

  67. E. D. Murray, Jr., and S. Clarke. J. Biol. Chem. 259:10722–10732 (1984).

    Google Scholar 

  68. K. Bedii Oray, U. Yuksel, and R. W. Gracy. J. Chromatogr. 265:126–130 (1983).

    Google Scholar 

  69. T. Baba, H. Sugiyama, and S. Seto. Chem. Pharm. Bull. 21:207–209 (1973).

    Google Scholar 

  70. P. A. Khairallah, F. M. Bumpus, J. H. Page, and R. R. Smeby. Science 140:672–674 (1963).

    Google Scholar 

  71. C. Secchi, P. A. Biondi, A. Negri, R. Borroni, and S. Ronchi. Int. J. Peptide Protein Res. 28:298–306 (1986).

    Google Scholar 

  72. S. Clarke. In R. T. Borchardt, C. R. Creveling, and P. M. Ueland (eds.), Biological Methylation and Drug Design, Humana Press, Clifton, N.J., 1985, pp. 3–14.

    Google Scholar 

  73. B. A. Johnson, J. M. Shirokawa, and D. W. Aswad. Arch. Biochem. Biophys. 268:276–286 (1989).

    Google Scholar 

  74. H. B. F. Dixon, S. Moore, M. P. Stack-Dunne, and F. G. Young. Nature 168:1044–1045 (1951).

    Google Scholar 

  75. F. A. Kuehl, Jr., M. A. P. Meisinger, N. G. Brink, and K. Folkers. J. Am. Chem. Soc. 75:1955–1959 (1953).

    Google Scholar 

  76. H. Rasmussen and L. C. Craig. Recent Prog. Horm. Res. 18:269–295 (1962).

    Google Scholar 

  77. W. Vale, J. Spiess, C. Rivier, and J. Rivier. Science 213:1394–1397 (1981).

    Google Scholar 

  78. K. Norris, J. Halstrom, and K. Brunfeldt. Acta Chem. Scand. 25:945–954 (1971).

    Google Scholar 

  79. M. Coltrera, M. Rosenblatt, and J. T. Potts, Jr. Biochemistry 19:4380–4385 (1980).

    Google Scholar 

  80. G. E. Means and R. E. Feeney. In Chemical Modifications of Proteins, Holden-Day, New York, 1971, pp. 162–165.

    Google Scholar 

  81. N. Brot and H. Weissbach. Trends Biochem. Sci. 7:137–139 (1982).

    Google Scholar 

  82. Y. Shechter, Y. Burstein, and A. Patchornik. Biochemistry 14:4497–4503 (1975).

    Google Scholar 

  83. Y. Shechter. J. Biol. Chem. 261:66–70 (1986).

    Google Scholar 

  84. M. L. Dedman, T. H. Farmer, and C. J. O. R. Morris. Biochem. J. 78:348–352 (1961).

    Google Scholar 

  85. H. B. F. Dixon. Biochim. Biophys. Acta 19:392–394 (1956).

    Google Scholar 

  86. A. H. Tashjian, D. A. Ontjes, and P. L. Munson. Biochemistry 3:1175–1182 (1964).

    Google Scholar 

  87. J. S. Morley, H. J. Tracey, and R. A. Gregory. Nature 207:1356–1359 (1965).

    Google Scholar 

  88. V. B. Riniker, R. Neher, R. Maier, F. W. Kahnt, P. G. H. Byfield, T. V. Gudmundsson, L. Galante, and I. MacIntyre. Helv. Chem. Acta 51:1738–1742 (1968).

    Google Scholar 

  89. P. Caldwell, D. C. Luk, H. Weissbach, and N. Brot. Proc. Natl. Acad. Sci. USA 75:5349–5352 (1978).

    Google Scholar 

  90. H. Carp and A. Janoff. Am. Rev. Resp. Dis. 118:617–621 (1978).

    Google Scholar 

  91. W. R. Abrams, A. Eliraz, P. Kimbel, and G. Weinbaum. Exp. Lung Res. 1:211–223 (1980).

    Google Scholar 

  92. C. E. Stauffer and D. Etson. J. Biol. Chem. 244:5333–5338 (1969).

    Google Scholar 

  93. W. J. Ray, Jr., and D. E. Koshland, Jr. J. Biol. Chem. 237:2493–2505 (1962).

    Google Scholar 

  94. H. Schachter and G. H. Dixon. J. Biol. Chem. 239:813–829 (1964).

    Google Scholar 

  95. V. Holeysovsky and M. Lazdunski. Biochim. Biophys. Acta 154:457–467 (1968).

    Google Scholar 

  96. U. W. Kenkare and F. M. Richards. J. Biol. Chem. 241:3197–3206 (1966).

    Google Scholar 

  97. G. Jori, G. Galiazzo, A. Marzotto, and E. Scoffone. Biochim. Biophys. Acta 154:1–9 (1968).

    Google Scholar 

  98. G. Jori, G. Galiazzo, A. Marzotto, and E. Scoffone. J. Biol. Chem. 243:4272–4278 (1968).

    Google Scholar 

  99. N. P. Neumann, S. Moore, and W. H. Stein. Biochemistry 1:68–75 (1962).

    Google Scholar 

  100. H. Schachter, K. A. Halliday, and G. H. Dixon. J. Biol. Chem. 238:PC3134–PC3136 (1963).

    Google Scholar 

  101. B. Kassell. Biochemistry 3:152–155 (1964).

    Google Scholar 

  102. W. F. Heath and R. B. Merrifield. Proc. Natl. Acad. Sci. USA 83:6367–6371 (1986).

    Google Scholar 

  103. C. George-Nascimento, A. Gyenes, S. M. Halloran, J. Merryweather, P. Valenzuela, K. S. Steimer, F. R. Masiarz, and A. Randolph. Biochemistry 27:797–802 (1988).

    Google Scholar 

  104. S. A. Coolican, B. N. Jones, R. D. England, K. C. Flanders, J. D. Condit, and R. S. Gurd. Biochemistry 21:4974–4981 (1982).

    Google Scholar 

  105. L. C. Teh, L. J. Murphy, N. L. Huq, A. S. Surus, H. G. Friesen, L. Lazarus, and G. E. Chapman. J. Biol. Chem. 262:6472–6477 (1987).

    Google Scholar 

  106. H. G. Gundlach, S. Moore, and W. H. Stein. J. Biol. Chem. 234:1761–1764 (1959).

    Google Scholar 

  107. E. Gross and B. Witkop. J. Am. Chem. Soc. 83:1510–1511 (1961).

    Google Scholar 

  108. H. B. F. Dixon and M. P. Stack-Dunne. Biochem. J. 61:483–495 (1955).

    Google Scholar 

  109. T. B. Lo, J. S. Dixon, and C. H. Li. Biochim. Biophys. Acta 53:584–586 (1961).

    Google Scholar 

  110. H. P. J. Bennett, A. M. Hudson, C. McMartin, and G. E. Purdon. Biochem. J. 168:9–13 (1977).

    Google Scholar 

  111. D. C. Shaw and C. E. West. J. Chromatogr. 200:185–188 (1980).

    Google Scholar 

  112. P. I. Storring and R. J. Tiplady. Anal. Biochem. 141:43–54 (1984).

    Google Scholar 

  113. P. C. Jocelyn. Biochemistry of the SH Groups: The Occurrence, Chemical Properties, Metabolism, and Biological Function of Thiols and Disulfides, Academic Press, New York, 1972.

    Google Scholar 

  114. C. Little and P. J. O'Brien. Arch. Biochem. Biophys. 122:406–410 (1967).

    Google Scholar 

  115. H. Lamfrom and S. O. Nielson. J. Am. Chem. Soc. 79:1966–1970 (1957).

    Google Scholar 

  116. D. Cavallini, C. DeMarco, and S. Dupre. Arch. Biochem. Biophys. 124:18–26 (1968).

    Google Scholar 

  117. E. S. G. Barron, Z. B. Miller, and G. Kalnitsky. Biochem. J. 41:62–68 (1947).

    Google Scholar 

  118. C. G. Overberger and J. J. Ferraro. J. Org. Chem. 27:3539–3545 (1962).

    Google Scholar 

  119. L. Philipson. Biochim. Biophys. Acta 56:375–377 (1962).

    Google Scholar 

  120. S. J. Tomazic and A. M. Klibanov. J. Biol. Chem. 263:3086–3091 (1988).

    Google Scholar 

  121. Y. M. Torchinskii. In Sulfhydryl and Disulfide Groups of Proteins, Consultants Bureau, New York, 1974, pp. 99–124.

    Google Scholar 

  122. L. A. Æ. Sluyterman. Biochim. Biophys. Acta 60:557–561 (1962).

    Google Scholar 

  123. B. R. DasGupta and D. A. Boroff. Biochim. Biophys. Acta 97:157–159 (1965).

    Google Scholar 

  124. L. Weil. Arch. Biochem. Biophys. 110:57–68 (1965).

    Google Scholar 

  125. J. D. Spikes and R. Straight. Annu. Rev. Phys. Chem. 18:49–436 (1967).

    Google Scholar 

  126. C. S. Foote. Science 162:963 (1968).

    Google Scholar 

  127. W. J. Ray. Methods Enzymol. 11:490–497 (1967).

    Google Scholar 

  128. P. Hoffee, C. Y. Lai, E. L. Pugh, and B. L. Horecker. Proc. Natl. Acad. Sci. USA 57:107–113 (1967).

    Google Scholar 

  129. M. Martinez-Carrion, R. Kuczenski, D. C. Tiemeier, and D. L. Peterson. J. Biol. Chem. 245:799–805 (1970).

    Google Scholar 

  130. M. Martinez-Carrion, C. Turano, F. Riva, and P. Fasella. J. Biol. Chem. 242:1426–1430 (1967).

    Google Scholar 

  131. M. Nakatani. J. Biochem. (Tokyo) 48:633–639 (1960).

    Google Scholar 

  132. R. D. Hill and R. R. Laing. Biochim. Biophys. Acta 99:352–359 (1965).

    Google Scholar 

  133. J. Schulz. Methods Enzymol. 11:255–263 (1967).

    Google Scholar 

  134. A. Light. Methods Enzymol. 11:417–420 (1967).

    Google Scholar 

  135. A. S. Inglis. Methods Enzymol. 91:324–332 (1983).

    Google Scholar 

  136. D. Piszkiewicz, M. Landon, and E. L. Smith. Biochem. Biophys. Res. Commun. 40:1173–1178 (1970).

    Google Scholar 

  137. K. Poulsen, K. J. Kevin, and E. Haber. Proc. Natl. Acad. Sci. USA 69:2495–2499 (1972).

    Google Scholar 

  138. F. Marcus. Int. J. Peptide Protein Res. 25:542–546 (1985).

    Google Scholar 

  139. D. L. Swallow and E. P. Abraham. Biochem. J. 70:364–373 (1958).

    Google Scholar 

  140. M. A. Naughton, F. Sanger, B. S. Hartley, and D. C. Shaw. Biochem. J. 77:149–163 (1960).

    Google Scholar 

  141. M. Bodanszky, G. F. Sigler, and A. Bodanszky. J. Am. Chem. Soc. 95:2352–2357 (1973).

    Google Scholar 

  142. M. Bodanszky, M. A. Ondetti, S. D. Levine, and N. J. Williams. J. Am. Chem. Soc. 89:6753–6757 (1967).

    Google Scholar 

  143. K. K. Han, C. Richard, and G. Biserte. Int. J. Biochem. 15:875–884 (1983).

    Google Scholar 

  144. P. Desnuelle and A. Casal. Biochim. Biophys. Acta 2:64–75 (1948).

    Google Scholar 

  145. U. K. Laemmli. Nature 227:680–685 (1970).

    PubMed  Google Scholar 

  146. J. B. Fleischman. Immunochemistry 10:401–407 (1973).

    Google Scholar 

  147. V. Braun and W. A. Schroeder. Arch. Biochem. Biophys. 118:241–252 (1967).

    Google Scholar 

  148. W. R. Gray. Methods Enzymol. 25:121–138 (1972).

    Google Scholar 

  149. J. L. Meuth. Biochemistry 21:3750–3757 (1982).

    Google Scholar 

  150. P. Edman and G. Begg. Eur. J. Biochem. 1:80–91 (1967).

    Google Scholar 

  151. K. A. Walsh, L. H. Ericsson, D. C. Parmelee, and K. Titani. Annu. Rev. Biochem. 50:261–284 (1981).

    Google Scholar 

  152. D. Kahne and W. C. Still. J. Am. Chem. Soc. 110:7529–7534 (1988).

    Google Scholar 

  153. R. Cecil and J. R. McPhee. Adv. Protein Chem. 14:255–389 (1959).

    Google Scholar 

  154. V. L. Lumper and H. Zahn. Adv. Enzymol. Relat. Areas Mol. Biol. 27:199–238 (1965).

    Google Scholar 

  155. D. B. Volkin and A. M. Klibanov. J. Biol. Chem. 262:2945–2950 (1987).

    Google Scholar 

  156. R. E. Benesch and R. Benesch. J. Am. Chem. Soc. 80:1666–1669 (1958).

    Google Scholar 

  157. A. P. Ryle and F. Sanger. Biochem. J. 60:535–540 (1955).

    Google Scholar 

  158. Y. M. Torchinsky. In Sulfur in Proteins, Pergamon Press, New York, 1981, pp. 82–86.

    Google Scholar 

  159. E. Haber and C. B. Anfinsen. J. Biol. Chem. 237:1839–1844 (1962).

    Google Scholar 

  160. A. Galat, T. E. Creighton, R. C. Lord, and E. R. Blout. Biochemistry 20:594–601 (1981).

    Google Scholar 

  161. A. Neuberger. Adv. Protein Chem. 4:297–383 (1948).

    Google Scholar 

  162. G. G. Smith and B. S. Desol. Science 207:765–767 (1980).

    Google Scholar 

  163. M. Friedman and P. M. Masters. J. Food Sci. 47:760 (1982).

    Google Scholar 

  164. P. J. M. van den Oestelaar and H. J. Hoenders. Adv. Exp. Med. Biol. 231:261–267 (1988).

    Google Scholar 

  165. T. M. Florence. Biochem. J. 189:507–520 (1980).

    Google Scholar 

  166. J. R. Whitaker and R. E. Feeney. CRC Crit. Rev. Food Sci. Nutr. 19:173–212 (1983).

    Google Scholar 

  167. L. C. Sen, E. Gonzalez-Flores, R. E. Feeney, and J. R. Whitaker. J. Agr. Food Chem. 25:632–638 (1977).

    Google Scholar 

  168. H. S. Lee, D. T. Osuga, A. S. Nashef, A. I. Ahmed, J. R. Whitaker, and R. E. Feeney. J. Agr. Food Chem. 25:1153–1158 (1977).

    Google Scholar 

  169. A. S. Nashef, D. T. Osuga, H. S. Lee, A. I. Ahmed, J. R. Whitaker, and R. E. Feeney. J. Agr. Food Chem. 25:245–251 (1977).

    Google Scholar 

  170. T. E. Creighton. Proteins, W. H. Freeman, New York, 1983.

    Google Scholar 

  171. C. Ghelis and J. Yon. Protein Folding, Academic Press, New York, 1982.

    Google Scholar 

  172. W. Kauzmann. Adv. Protein Chem. 14:1–63 (1959).

    Google Scholar 

  173. P. L. Privalov. Adv. Protein Chem. 33:167 (1979).

    Google Scholar 

  174. K. Dill. Biochemistry 24:1501–1509 (1985).

    Google Scholar 

  175. Y. R. Hsu and T. Arakawa. Biochemistry 24:7959–7963 (1985).

    Google Scholar 

  176. T. Arakawa and W. C. Kenney. Int. J. Peptide Protein Res. 31:468–473 (1988).

    Google Scholar 

  177. T. Arakawa, T. Boone, J. M. Davis, and W. C. Kenney. Biochemistry 25:8274–8277 (1986).

    Google Scholar 

  178. T. Arakawa, Y.-R. Hsu, and D. A. Yphantis. Biochemistry 26:5428–5432 (1987).

    Google Scholar 

  179. W. W. Fish, A. Danielsson, K. Nordling, S. H. Miller, C. F. Lam, and I. Björk. Biochemistry 24:1510–1517 (1985).

    Google Scholar 

  180. D. N. Brems, S. M. Plaisted, E. W. Kauffman, and H. A. Havel. Biochemistry 25:6539–6543 (1986).

    Google Scholar 

  181. T. F. Holzman, D. N. Brems, and J. J. Dougherty, Jr. Biochemistry 25:6907–6917 (1986).

    Google Scholar 

  182. D. N. Brems, S. M. Plaisted, H. A. Havel, and C.-S. C. Tomich. Proc. Natl. Acad. Sci. USA 85:3367–3371 (1988).

    Google Scholar 

  183. D. N. Brems. Biochemistry 27:4541–4546 (1988).

    Google Scholar 

  184. Y. Goto and A. L. Fink. Biochemistry 28:945–952 (1989).

    Google Scholar 

  185. J. Baum, C. M. Dobson, P. A. Evans, and C. Hanley. Biochemistry 28:7–13 (1989).

    Google Scholar 

  186. D. N. Brems, S. M. Plaisted, J. J. Dougerty, Jr., and T. F. Holzman. J. Biol. Chem. 262:2590–2594 (1987).

    Google Scholar 

  187. D. N. Brems, S. M. Plaisted, H. A. Havel, E. W. Kauffman, J. D. Stodola, L. C. Eaton, and R. C. White. Biochemistry 24:7662–7668 (1985).

    Google Scholar 

  188. H. A. Havel, E. W. Kauffman, S. M. Plaisted, and D. N. Brems. Biochemistry 25:6533–6538 (1986).

    Google Scholar 

  189. W. Pfeil. Mol. Cell. Biochem. 40:2–38 (1981).

    Google Scholar 

  190. M. P. Tombs. J. Appl. Biochem. 7:3–24 (1985).

    Google Scholar 

  191. W. J. Becktel and J. A. Schellman. Biopolymers 26:1859–1877 (1987).

    Google Scholar 

  192. C. Tanford. Adv. Protein Chem. 23:121–282 (1968).

    Google Scholar 

  193. J. A. Schellman. Annu. Rev. Biophys. Biophys. Chem. 16:115–137 (1987).

    Google Scholar 

  194. C. N. Pace. CRC Crit. Rev. Biochem. 3:1–43 (1975).

    Google Scholar 

  195. H. Neurath, J. P. Greenstein, F. W. Putnam, and J. O. Erickson. Chem. Rev. 34:157–265 (1944).

    Google Scholar 

  196. J. M. Thornton. J. Mol. Biol. 151:261–287 (1981).

    Google Scholar 

  197. T. J. Ahern and A. M. Klibanov. Meth. Biochem. Anal. 33:91–127 (1985).

    Google Scholar 

  198. C. B. Anfinsen and H. A. Scheraga. Adv. Protein Chem. 29:205–300 (1975).

    Google Scholar 

  199. T. E. Creighton. Prog. Biophys. Mol. Biol. 33:231–297 (1978).

    Google Scholar 

  200. P. L. Privalov. Adv. Protein Chem. 35:1 (1982).

    Google Scholar 

  201. J. F. Brandts. In S. N. Timasheff and G. D. Fasman (eds.), Biological Macromolecules Series, Vol. 2, Structure and Stability of Biological Macromolecules, Marcel Dekker, New York, 1967, p. 213.

    Google Scholar 

  202. R. Wetzel, L. J. Perry, W. A. Baase, and W. J. Becktel. Proc. Natl. Acad. Sci. USA 85:401–405 (1988).

    Google Scholar 

  203. W. J. Becktel and W. A. Baase. Biopolymers 26:619–623 (1987).

    Google Scholar 

  204. J. Novotny, A. A. Rashin, and R. E. Bruccoleri. Proteins: Structure, Function, Genetics 4:19–30 (1988).

    Google Scholar 

  205. M. H. Zehfus and G. D. Rose. Biochemistry 25:5759–5765 (1986).

    Google Scholar 

  206. S. H. Bryant and L. M. Anzel. Int. J. Peptide Protein Res. 29:46–52 (1986).

    Google Scholar 

  207. A. M. Klibanov. Adv. Appl. Microbiol. 29:1–28 (1983).

    Google Scholar 

  208. R. Lumry and H. Eyring. J. Phys. Chem. 58:110–120 (1954).

    Google Scholar 

  209. T. Arakawa, N. K. Alton, and Y.-R. Hsu. J. Biol. Chem. 260:14435–14439 (1985).

    Google Scholar 

  210. D. A. Yphantis and T. Arakawa. Biochemistry 26:5422–5427 (1987).

    Google Scholar 

  211. T. Hoshino, Y. Mikura, H. Shimidzu, J. Kawai, and H. Toguchi. Biochim. Biophys. Acta 916:245–250 (1987).

    Google Scholar 

  212. T. A. Horbett. ACS Adv. Chem. Ser. 199:233–244 (1982).

    Google Scholar 

  213. T. A. Horbett. ACS Symp. Ser. 343:239–260 (1987).

    Google Scholar 

  214. J. R. Brennan, S. S. P. Gebhart, and W. G. Blackard. Diabetes 34:353–359 (1985).

    Google Scholar 

  215. D. E. James, A. B. Jenkins, E. W. Kraegen, and D. J. Chisholm. Diabetologia 21:554–557 (1981).

    Google Scholar 

  216. W. D. Lougheed, H. Woulfe-Flanagan, J. R. Clement, and A. M. Albisser. Diabetologia 19:1–9 (1980).

    Google Scholar 

  217. L. Peterson, J. Caldwell, and J. Hoffman. Diabetes 25:72–74 (1976).

    Google Scholar 

  218. M. V. Sefton. ACS Adv. Chem. Ser. 199:511–522 (1982).

    Google Scholar 

  219. A. S. Chawla, I. Hinberg, P. Blais, and D. Johnson. Diabetes 34:420–424 (1985).

    Google Scholar 

  220. G. K. Iwamoto, R. A. Van Wagenen, and J. D. Andrade. J. Colloid Interface Sci. 86:581–585 (1982).

    Google Scholar 

  221. E. H. Massey and T. A. Sheliga. Pharm. Res. 5:S34 (1988).

    Google Scholar 

  222. W. D. Lougheed, A. M. Albisser, H. M. Martindale, J. C. Chow, and J. R. Clement. Diabetes 32:424–432 (1983).

    Google Scholar 

  223. S. Sato, C. D. Ebert, and S. W. Kim. J. Pharm. Sci. 72:228–232 (1983).

    Google Scholar 

  224. Z. J. Twardowski, K. D. Nolph, T. J. McGary, and H. L. Moore. Am. J. Hosp. Pharm. 40:583–586 (1983).

    Google Scholar 

  225. Z. J. Twardowski, K. D. Nolph, T. J. McGary, H. L. Moore, P. Collin, R. K. Ausman, and W. S. Slimack. Am. J. Hosp. Pharm. 40:575–579 (1983).

    Google Scholar 

  226. Z. J. Twardowski, K. D. Nolph, T. J. McGary, and H. L. Moore. Am. J. Hosp. Pharm. 40:579–581 (1983).

    Google Scholar 

  227. M. L. Anson. In C. L. A. Schmidt (ed.), The Chemistry of the Amino Acids and Proteins, Charles Thomas, Springfield, Ill., 1938, pp. 407–428.

    Google Scholar 

  228. A. E. Mirsky and L. Pauling. Proc. Natl. Acad. Sci. USA 22:439–447 (1936).

    Google Scholar 

  229. J. K. Krueger, M. H. Kulke, C. Schutt, and J. Stock. BioPharm. Mar.:41–45 (1989).

  230. F. A. O. Marston. Biochem. J. 240:1–12 (1986).

    Google Scholar 

  231. J. M. Schoemaker, A. H. Brasnett, and F. A. O. Marston. EMBO J. 4:775–780 (1985).

    Google Scholar 

  232. D. L. Hartley and J. F. Kane. Biochem. Soc. Trans. 16:101–102 (1988).

    Google Scholar 

  233. D. C. Williams, R. M. Van Frank, W. L. Muth, and J. P. Burnett. Science 215:687 (1982).

    Google Scholar 

  234. J. King. Bio/technology 4:297–303 (1986).

    Google Scholar 

  235. M. Gribskov and R. R. Burgess. Gene 26:109–118 (1983).

    Google Scholar 

  236. F. A. O. Marston, P. A. Lowe, M. T. Doel, J. M. Schoemaker, S. White, and S. Angal. Bio/technology 2:800–804 (1984).

    Google Scholar 

  237. S. Cabilly, A. D. Riggs, H. Pande, J. E. Shirely, W. E. Holmes, M. Rey, L. J. Perry, R. Wetzel, and H. L. Heynecker. Proc. Natl. Acad. Sci. USA 81:3273–3277 (1984).

    Google Scholar 

  238. M. E. Winkler, M. Blabel, G. L. Bennett, W. Holmes, and G. A. Vehar. Bio/technology 3:990–1000 (1985).

    Google Scholar 

  239. H. J. George, J. J. L'Italien, W. P. Pilancinski, D. L. Glassman, and R. A. Krzyzek. DNA 4:273–281 (1985).

    Google Scholar 

  240. R. C. Fahey, J. S. Hunt, and G. C. Winham. J. Mol. Evol. 10:155–160 (1977).

    Google Scholar 

  241. T. Arakawa and S. N. Timasheff. Biochemistry 23:5912–5923 (1984).

    Google Scholar 

  242. T. Arakawa and S. N. Timasheff. Biochemistry 21:6545–6552 (1982).

    Google Scholar 

  243. F. Ahmad and C. C. Bigelow. J. Protein Chem. 5:355–367 (1986).

    Google Scholar 

  244. R. Bhat and J. C. Ahluwalia. Int. J. Peptide Protein Res. 30:145–152 (1985).

    Google Scholar 

  245. F. Ahmad. Can J. Biochem. Cell Biol. 63:1058–1063 (1985).

    Google Scholar 

  246. R. Almog. Biophys. Chem. 17:111–118 (1983).

    Google Scholar 

  247. E. Stellwagen and J. Babul. Biochemistry 14:5135–5140 (1975).

    Google Scholar 

  248. L. O. Narhi, M. K. Zukowski, and T. Arakawa. Biophys. J. 55:23a (1989).

    Google Scholar 

  249. M. W. Pantoliano, M. Whitlow, J. F. Wood, M. L. Rollence, B. C. Finzel, G. L. Gilliland, T. L. Poulos, and P. N. Bryant. Biochemistry 27:8311–8317 (1988).

    Google Scholar 

  250. A. J. Russell and A. R. Fersht. Nature 328:496–500 (1987).

    Google Scholar 

  251. C. N. Pace and G. R. Grimsley. Biochemistry 27:3242–3246 (1988).

    Google Scholar 

  252. F. W. Dahlquist, J. W. Long, and W. L. Bigbee. Biochemistry 15:1103–1111 (1976).

    Google Scholar 

  253. G. Voordouw, C. Milo, and R. S. Roche. Biochemistry 15:3716–3724 (1976).

    Google Scholar 

  254. V. V. Filimonov, W. Pfeil, T. N. Tsalkova, and P. L. Privalov. Biophys. Chem. 8:117–122 (1978).

    Google Scholar 

  255. H. Schulz. FEBS Lett. 78:303–308 (1977).

    Google Scholar 

  256. J. F. Chlebowski, S. Mabrey, and M. C. Falk. J. Biol. Chem. 254:5745–5753 (1979).

    Google Scholar 

  257. J. F. Chlebowski and S. Mabrey. J. Biol. Chem. 252:7042–7050 (1977).

    Google Scholar 

  258. S. Linse, P. Brodin, C. Johansson, E. Thulin, T. Grundström, and S. Forsén. Nature 335:651–653 (1988).

    Google Scholar 

  259. E. Stellwagen and H. Wilgus. In S. M. Friedman (ed.), Biochemistry of Thermophily, Academic Press, New York, 1978, pp. 228–232.

    Google Scholar 

  260. J. A. Roe, A. Butler, D. M. Scholler, J. S. Valentine, L. Marky, and K. J. Breslauer. Biochemistry 27:950–958 (1988).

    Google Scholar 

  261. Y. Hiroka, T. Segawa, K. Kawajima, S. Sugai, and N. Murai. Biochem. Biophys. Res. Commun. 95:1098–1104 (1980).

    Google Scholar 

  262. M. Mitani, Y. Harushima, K. Kawajima, M. Ikeguchi, and S. Sugai. J. Biol. Chem. 261:8824–8829 (1986).

    Google Scholar 

  263. J. Desmet, I. Hanssens, and F. van Cauwelaert. Biochim. Biophys. Acta 912:211–219 (1987).

    Google Scholar 

  264. R. Palmieri, R. W.-K. Lee, and M. F. Dunn. Biochemistry 27:3387–3397 (1988).

    Google Scholar 

  265. K. Gekko and S. N. Timasheff. Biochemistry 20:4667–4676 (1981).

    Google Scholar 

  266. K. Gekko and S. N. Timasheff. Biochemistry 20:4677–4686 (1981).

    Google Scholar 

  267. J. C. Lee and S. N. Timasheff. J. Biol. Chem. 256:7193–7201 (1981).

    Google Scholar 

  268. J. C. Lee and S. N. Timasheff. Biochemistry 13:257–265 (1974).

    Google Scholar 

  269. J. C. Lee and S. N. Timasheff. Biochemistry 14:5183–5187 (1975).

    Google Scholar 

  270. S. N. Timasheff, J. C. Lee, E. P. Pittz, and N. Tweedy. J. Colloid Interface Sci. 55:658–663 (1976).

    Google Scholar 

  271. J. C. Lee and S. N. Timasheff. Biochemistry 16:1754–1764 (1977).

    Google Scholar 

  272. I. D. Kuntz, Jr., and W. Kauzmann. Adv. Protein Chem. 28:239–345 (1974).

    Google Scholar 

  273. V. Prakesh, P. K. Nandi, and B. Jirgensons. Int. J. Peptide Protein Res. 15:305–313 (1980).

    Google Scholar 

  274. B. Jirgensons. J. Protein Chem. 1:71 (1982).

    Google Scholar 

  275. B. Jirgensons. Macromol. Chem. Rapid Commun. 2:213–217 (1981).

    Google Scholar 

  276. F. F. Shih and A. D. Kalmar. J. Agr. Food Chem. 35:672–675 (1987).

    Google Scholar 

  277. K. Takeda, K. Sasa, M. Nagao, and P. P. Batra. Biochim. Biophys. Acta 957:340–344 (1988).

    Google Scholar 

  278. K. Fukushima, Y. Murata, N. Nishikido, G. Sugihara, and M. Tanaka. Bull. Chem. Soc. Jap. 54:3122–3127 (1981).

    Google Scholar 

  279. J. L. Bohnert and T. A. Horbett. J. Colloid Interface Sci. 111:363–377 (1986).

    Google Scholar 

  280. J. Piatigorsky, J. Horwitz, and R. T. Simpson. Biochim. Biophys. Acta 490:279–289 (1977).

    Google Scholar 

  281. S. Tandon and P. M. Horowitz. J. Biol. Chem. 262:4486–4491 (1987).

    Google Scholar 

  282. P. S. Banerjee and W. A. Ritschel. J. Pharm. Sci. 76:S48 (1987).

    Google Scholar 

  283. A. L. Daugherty, H. D. Liggitt, J. G. McCabe, J. A. Moore, and J. S. Patton. Int. J. Pharm. 45:197–206 (1988).

    Google Scholar 

  284. D. Shortle. J. Biol. Chem. 264:5315–5318 (1989).

    Google Scholar 

  285. E. Querol and A. Padilla. Enzyme Microbial Technol. 9:238–244 (1987).

    Google Scholar 

  286. M. H. Hecht, J. M. Sturtevant, and R. T. Sauer. Proteins Struct. Funct. Genet. 1:43–46 (1986).

    Google Scholar 

  287. P. J. Carter, G. Winter, A. J. Wilkinson, and A. R. Fersht. Cell 38:835–840 (1984).

    Google Scholar 

  288. B. W. Matthews, H. Nicholson, and W. J. Becktel. Proc. Natl. Acad. Sci. USA 84:6663–6667 (1987).

    Google Scholar 

  289. G. N. Ramachandran and V. Sasisekharan. Adv. Protein Chem. 23:283–437 (1968).

    Google Scholar 

  290. S. K. Burley and G. A. Petsko. Science 225:23–28 (1985).

    Google Scholar 

  291. S. K. Burley and G. A. Petsko. Adv. Protein Chem. 39:125–189 (1988).

    Google Scholar 

  292. J. T. Kellis, Jr., K. Nyberg, D. Sali, and A. R. Fersht. Nature 333:784–786 (1988).

    Google Scholar 

  293. M. Matsumura, W. J. Becktel, and B. W. Matthews. Nature 334:406–410 (1988).

    Google Scholar 

  294. T. Alber, S. Dao-pin, K. Wilson, J. A. Wozniak, S. P. Cook, and B. W. Matthews. Nature 330:41–46 (1987).

    Google Scholar 

  295. J. F. Reidhaar-Olson and R. T. Sauer. Science 241:53–57 (1988).

    Google Scholar 

  296. M. L. Elwell and J. A. Schellman. Biochim. Biophys. Acta 494:367–383 (1977).

    Google Scholar 

  297. M. H. Hecht, J. M. Sturtevant, and R. T. Sauer. Proc. Natl. Acad. Sci. USA 81:5685–5689 (1984).

    Google Scholar 

  298. D. Shortle and A. K. Meeker. Proteins Struct. Funct. Genet. 1:81–89 (1986).

    Google Scholar 

  299. D. Shortle and A. K. Meeker. Biochemistry 28:936–944 (1989).

    Google Scholar 

  300. H. Nicholson, W. J. Becktel, and B. W. Matthews. Nature 336:651–656 (1988).

    Google Scholar 

  301. R. Hawkes, M. G. Grutter, and J. Schellman. J. Mol. Biol. 175:195–212 (1984).

    Google Scholar 

  302. M. Grutter, R. Hawkes, and B. Matthews. Nature 277:667–669 (1979).

    Google Scholar 

  303. W. J. Becktel, W. A. Baase, B. L. Chen, D. C. Muchmore, C. G. Schellman, and J. A. Schellman. Biophys. J. 49:572a (1986).

    Google Scholar 

  304. M. Grutter and B. Matthews. J. Mol. Biol. 154:525–535 (1982).

    Google Scholar 

  305. T. Alber, S. Dao-pin, J. A. Nye, D. C. Muchmore, and B. W. Matthews. Biochemistry 26:3754–3758 (1987).

    Google Scholar 

  306. B. W. Matthews. Biochemistry 26:6885–6887 (1987).

    Google Scholar 

  307. W. G. J. Hol, P. T. van Duijnen, and H. J. C. Berendsen. Nature 273:443–446 (1978).

    Google Scholar 

  308. W. G. J. Hol. Prog. Biophys. Mol. Biol. 45:149–195 (1985).

    Google Scholar 

  309. W. G. J. Hol. Angew. Chem. Int. Ed. Engl. 25:767–778 (1986).

    Google Scholar 

  310. W. G. J. Hol, L. M. Halie, and C. Sander. Nature 294:532–536 (1981).

    Google Scholar 

  311. R. P. Sheridan, R. M. Levy, and F. R. Salemme. Proc. Natl. Acad. Sci. USA 80:4545–4549 (1982).

    Google Scholar 

  312. K.-C. Chou, G. M. Maggiora, G. Nemethy, and H. A. Scheraga. Proc. Natl. Acad. Sci. USA 85:4295–4299 (1988).

    Google Scholar 

  313. J. S. Richardson. Adv. Protein Chem. 34:167–339 (1981).

    Google Scholar 

  314. P. S. Kim and R. L. Baldwin. Nature 307:329–334 (1984).

    Google Scholar 

  315. K. R. Shoemaker, P. S. Kim, D. N. Brems, S. Marqusee, E. J. York, I. M. Chaiken, J. M. Stewart, and R. L. Baldwin. Proc. Natl. Acad. Sci. USA 82:2349–2353 (1985).

    Google Scholar 

  316. C. Mitchinson and R. L. Baldwin. Proteins Struct. Funct. Genet. 1:23–33 (1986).

    Google Scholar 

  317. K. G. Strehlow and R. L. Baldwin. Biochemistry 28:2130–2133 (1989).

    Google Scholar 

  318. S. Marqusee and R. L. Baldwin. Proc. Natl. Acad. Sci. USA 84:8898–8902 (1987).

    Google Scholar 

  319. H. A. Scheraga. Proc. Natl. Acad. Sci. USA 82:5585–5587 (1985).

    Google Scholar 

  320. M. F. Perutz and G. Fermi. Proteins Struct. Funct. Genet. 4:294–295 (1988).

    Google Scholar 

  321. P. C. Lyu, L. A. Marky, and N. R. Kallenbach. J. Am. Chem. Soc. 111:2733–2734 (1989).

    Google Scholar 

  322. R. J. Abraham, B. D. Hudson, W. A. Thomas, and A. Krohn. J. Mol. Graph. 4:28–32 (1986).

    Google Scholar 

  323. D. Sali, M. Bycroft, and A. R. Fersht. Nature 335:740–743 (1988).

    Google Scholar 

  324. W. J. Becktel, W. A. Baase, R. Wetzel, and L. J. Perry. Biophys. J. 49:109a (1986).

    Google Scholar 

  325. M. H. Hecht, K. M. Hehir, H. C. M. Nelson, J. M. Sturtevant, and R. T. Sauer. J. Cell. Biochem. 29:217–224 (1985).

    Google Scholar 

  326. J. E. Villafranca, E. E. Howell, D. H. Voet, M. S. Strobel, R. C. Ogden, J. N. Abelson, and J. Kraut. Science 222:782–788 (1983).

    Google Scholar 

  327. J. A. Wells and D. B. Powers. J. Biol. Chem. 261:6564–6570 (1986).

    Google Scholar 

  328. M. W. Pantoliano, R. C. Ladner, P. N. Bryan, M. L. Rollence, J. F. Wood, and T. L. Poulos. Biochemistry 26:2077–2082 (1987).

    Google Scholar 

  329. R. T. Sauer, K. Hehir, R. S. Stearman, M. A. Weiss, A. Jeitler-Nilsson, E. G. Suchanek, and C. O. Pabo. Biochemistry 25:5992–5998 (1986).

    Google Scholar 

  330. M. Matsumura and B. W. Matthews. Science 243:792–794 (1989).

    Google Scholar 

  331. L. J. Perry and R. Wetzel. Science 226:555–557 (1984).

    Google Scholar 

  332. L. J. Perry and R. Wetzel. Biochemistry 25:733–739 (1986).

    Google Scholar 

  333. M. G. Mulkerrin, L. J. Perry, and R. Wetzel. In D. L. Oxender (ed.), Protein Structure, Folding, and Design, Alan Liss, New York, 1986, pp. 297–305.

    Google Scholar 

  334. G. McLendon and E. Radany. J. Biol. Chem. 253:6335–6337 (1978).

    Google Scholar 

  335. T. J. Ahern, J. I. Casal, G. A. Petsko, and A. M. Klibanov. Proc. Natl. Acad. Sci. USA 84:675–679 (1987).

    Google Scholar 

  336. P. T. Wingfield, R. J. Mattaliano, H. R. MacDonald, S. Craig, G. M. Clore, A. M. Gronenborn, and U. Schmeissner. Protein Eng. 1:413–417 (1987).

    Google Scholar 

  337. A. Abuchowski. J. Cell. Biochem. 11A:174 (1987).

    Google Scholar 

  338. P. Koziej, M. Mutter, H.-U. Gremlich, and G. Hölzemann. Z. Naturforsch. 40B:1570–1574 (1985).

    Google Scholar 

  339. M. Mutter, H. Mutter, R. Uhlmann, and E. Bayer. Biopolymers 15:917–927 (1976).

    Google Scholar 

  340. P. V. N. Rajasekharan and M. Mutter. Acc. Chem. Res. 14:122–130 (1981).

    Google Scholar 

  341. A. A. Ribiero, R. P. Saltman, M. Goodman, and M. Mutter. Biopolymers 21:2225–2239 (1982).

    Google Scholar 

  342. M. Hashimoto, K. Takada, Y. Kiso, and S. Muanishi. Pharm. Res. 6:171–176 (1989).

    Google Scholar 

  343. D. D. Chow and K. J. Hwang. J. Pharm. Sci. 76:S49 (1987).

    Google Scholar 

  344. E. R. Jakoi, P. E. Ross, H. P. Ting-Beall, B. Kaufman, and T. C. Vanaman. J. Biol. Chem. 262:1300–1304 (1987).

    Google Scholar 

  345. D. A. Towler, S. R. Eubanks, D. S. Towery, S. P. Adams, and L. Glaser. J. Biol. Chem. 262:1030–1036 (1987).

    Google Scholar 

  346. Y. A. Ovchinnikov, N. G. Abdulaev, and A. S. Bogachuk. FEBS Lett. 230:1–5 (1988).

    Google Scholar 

  347. F. S. Qaw and J. M. Brewer. Mol. Cell. Biochem. 71:121–127 (1986).

    Google Scholar 

  348. A. T. Fojo, P. L. Whitney, and M. W. Awad, Jr. Arch. Biochem. Biophys. 224:636–642 (1983).

    Google Scholar 

  349. P. Cujo, W. El-Deiry, P. L. Whitney, and W. M. Awad, Jr. J. Biol. Chem. 255:10828–10833 (1980).

    Google Scholar 

  350. R. Wolfenden, L. Anderson, P. M. Cullis, and C. C. B. Southgate. Biochemistry 20:849–855 (1981).

    Google Scholar 

  351. R. Desrosiers and R. M. Tanguay. J. Biol. Chem. 263:4686–4692 (1988).

    Google Scholar 

  352. R. M. Epand and K. E. Raymer. Int. J. Peptide Protein Res. 30:515–521 (1987).

    Google Scholar 

  353. H. Koide, S. Yokoyama, G. Kawai, J.-M. Ha, T. Oka, S. Kawai, T. Miyake, T. Fuwa, and T. Miyazawa. Proc. Natl. Acad. Sci. USA 85:6237–6241 (1988).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas, 66045

    Mark C. Manning, Kamlesh Patel & Ronald T. Borchardt

Authors
  1. Mark C. Manning
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kamlesh Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ronald T. Borchardt
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Manning, M.C., Patel, K. & Borchardt, R.T. Stability of Protein Pharmaceuticals. Pharm Res 6, 903–918 (1989). https://doi.org/10.1023/A:1015929109894

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1015929109894

Search

Navigation