New Technologies to Prolong Life-time of Peptide and Protein Drugs In vivo |
| |
Authors: | 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 |
| |
Institution: | (1) Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, 76100, Israel;(2) Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, 76100, Israel |
| |
Abstract: | 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 |
本文献已被 SpringerLink 等数据库收录! |
|