New Technologies to Prolong Life-time of Peptide and Protein Drugs In vivo
- 249 Downloads
Most peptide and protein drugs are short-lived species in vivo with a circulatory half-life of several minutes. This is particularly valid for non-glycosylated proteins with a molecular mass of less than 50 kDa. Since peptide/protein drugs are not absorbed orally, prolonged maintenance of therapeutically active drugs in the circulatory system is of primary clinical importance. Another major obstacle of injected polypeptide drugs is the elevated concentration of 100–1000 times above the therapeutical level that may be present in the circulatory system shortly after administration. Such overdosing may lead to undesirable side effects such as over-stimulation or down-regulation of receptor sites.
In this review we describe two new strategies that overcome these two problems of systemically injected peptide/protein drugs. The first strategy includes Fmoc and FMS derivatization of peptides, proteins and low molecular-weight drugs, converting them to inactive prodrugs that undergo reactivation with desirable pharmacokinetic patterns in body fluids. Based on this Fmoc/FMS-technology, we have developed a second strategy, reversible pegylation. Inactive pegylated peptide/protein drugs release the native active parental molecule at slow rates, and in homogeneous fashion under physiological conditions, thus facilitating prolonged therapeutic effects, following a single administration.
Keywordsdiabetes FMS-technology insulin peptide/protein drugs prodrugs prolongation reversible-pegylation
a conjugate of 2-sulfo-9-fluorenylmethoxycarbonyl and keyhole limpet hemocyanin
human growth hormone
high-performance liquid chromatography
human serum albumin
a conjugate of neutral-protamine Hagedorn and insulin
We thank Elana Friedman for typing the manuscript and Yigal Avivi for editing it. Y.S. is the incumbent of the C.H. Hollenberg Chair in Metabolic and Diabetes Research, and M.F. is the Lester Pearson Prof. of Protein Chemistry.
- Bailon P., Palleroni A., Schaffer C. A., Spence C. L., Fung W.-J., Porter J. E., et al. (2001) Rational design of a potent, long-lasting form of interferon: a 40 kDa branched polyethylene glycol-conjugated intereron α-2a for the treatment of hepatitis C. Bioconjugate Chem. 12:195–202CrossRefGoogle Scholar
- Baker E. N., Blundell T. L., Cutfield S. M., Dodson E. J., Dodson G. G., Hodgkin D. M. C. (1988) The structure of 2Zn pig insulin crystals at 1.5Å resolution. Philos. Trans. Roy. Soc. London 319:369–456Google Scholar
- Benet, L. Z., Mitchell T. R. and Scheiner L. B.: 1990, in L. Goodman, A. E. Gilman, T. W. Rall, A. S. Nies and G. M. Taylor (eds.), The Pharmacological Basis of Therapeutics, Pergamon, New York, pp. 3–32Google Scholar
- Benzi L., Cecchetti P., Ciccarone A., Pilo A., Di C. G., Navalesi R. (1994) Insulin degradation in vitro and in vivo: a comparative study in men. Evidence that immnoprecipitable, partially rebindable degradation products are released from cells and circulate in blood. Diabetes 43:297–304PubMedCrossRefGoogle Scholar
- Chap Z., Ishida T., Chou J., Hartley C. J., Entman M. L., Brandenburg D. et al. (1987) First-pass hepatic extraction and metabolic effects of insulin and insulin analogues. Am. J. Physiol. 252:209–217Google Scholar
- Fung W.-J., Porter J. E., Bailon P. (1997) Strategies for the preparation and characterization of polyethylene glycol (PEG) conjugated pharmaceutical proteins. Polymer Preprints 38:565–566Google Scholar
- Hildebrant P. (1991) Subcutaneous absorption of insulin in insulin-dependent diabetic patients. Dan. Med. Bull. 38:337–346Google Scholar
- Kahn, C. R. and Shechter, Y.: 1990, Insulin, oral hypoglycemic agents and the pharmacology of the endocrine pancreas, in A. G. Gilman, T. W. Rall, A. S. Nies and P. Taylor (eds.), Goodman and Gilman Handbook of Pharmacology, New York/Oxford, Pergamon Press, pp. 1463–1495Google Scholar
- Lentner, C.: 1984, Geigy Scientific Tables. Basel, Switzerland, CIBA-GEIGY 69–71Google Scholar
- Means G. A., Feeney R. E. (1971) Chemical modification of proteins. Holden-Day, San FranciscoGoogle Scholar
- Peters, J. J.: 1996, Ligand binding to albumin, in All About Albumin: Biochemistry, Genetics and Medical Applications, Academic Press Inc., San Diego, pp. 76–132Google Scholar
- Shechter, Y., Tsubery, H., Mironchik, M., Rubinstein, M. and Fridkin, M.: 2005, Reversible PEGylation of peptide YY3–36 prolong its inhibition of food intake in mice. FEBS Lett. 2439–2444Google Scholar