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New Technologies to Prolong Life-time of Peptide and Protein Drugs In vivo

  • Y. Shechter
  • M. Mironchik
  • A. Saul
  • E. Gershonov
  • L. Precido-Patt
  • K. Sasson
  • H. Tsubery
  • B. Mester
  • A. Kapitkovsky
  • S. Rubinraut
  • Y. Vachutinski
  • G. Fridkin
  • M. Fridkin
Bruce Merrifield Commemorative Issue

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.

Keywords

diabetes FMS-technology insulin peptide/protein drugs prodrugs prolongation reversible-pegylation 

Abbreviations

Fmoc

9-fluorenylmethoxycarbonyl

FMS-KLH

a conjugate of 2-sulfo-9-fluorenylmethoxycarbonyl and keyhole limpet hemocyanin

FMS-OSu

2-sulfo-9-fluorenylmethoxycarbonyl-N-hydroxysuccinimide

hGH

human growth hormone

HPLC

high-performance liquid chromatography

HSA

human serum albumin

IFNα2

interferon-α2

LMW

low-molecular weight;

MAL-Fmoc-OSu

9-hydroxymethyl-2-(amino-3-maleimidopropionate)-fluorene-N-hydroxysuccinimide

MAL-FMS-OSu

2-sulfo-9-hydroxymethyl-7-(amino-3-maleimidopropionate)-fluorene-N-hydroxysuccinimide

NPH-insulin

a conjugate of neutral-protamine Hagedorn and insulin

PEG

polyethyleneglycol

STZ

streptozocin

Notes

Acknowledgments

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.

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Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Y. Shechter
    • 1
  • M. Mironchik
    • 1
  • A. Saul
    • 1
    • 2
  • E. Gershonov
    • 1
  • L. Precido-Patt
    • 1
    • 2
  • K. Sasson
    • 1
  • H. Tsubery
    • 1
    • 2
  • B. Mester
    • 1
    • 2
  • A. Kapitkovsky
    • 2
  • S. Rubinraut
    • 2
  • Y. Vachutinski
    • 1
    • 2
  • G. Fridkin
    • 1
  • M. Fridkin
    • 2
  1. 1.Department of Biological ChemistryWeizmann Institute of ScienceRehovotIsrael
  2. 2.Department of Organic ChemistryWeizmann Institute of ScienceRehovotIsrael

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