Strategies to improve plasma half life time of peptide and protein drugs |
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Authors: | M Werle A Bernkop-Schnürch |
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Institution: | (1) ThioMatrix GmbH, Research Center Innsbruck, Innsbruck, Austria;(2) Department of Pharmaceutical Technology, Leopold-Franzens-University, Innsbruck, Austria |
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Abstract: | Summary. Due to the obvious advantages of long-acting peptide and protein drugs, strategies to prolong plasma half life time of such
compounds are highly on demand. Short plasma half life times are commonly due to fast renal clearance as well as to enzymatic
degradation occurring during systemic circulation. Modifications of the peptide/protein can lead to prolonged plasma half
life times. By shortening the overall amino acid amount of somatostatin and replacing l-analogue amino acids with d-amino acids, plasma half life time of the derivate octreotide was 1.5 hours in comparison to only few minutes of somatostatin.
A PEG2,40 K conjugate of INF-α-2b exhibited a 330-fold prolonged plasma half life time compared to the native protein. It was the aim
of this review to provide an overview of possible strategies to prolong plasma half life time such as modification of N- and
C-terminus or PEGylation as well as methods to evaluate the effectiveness of drug modifications. Furthermore, fundamental
data about most important proteolytic enzymes of human blood, liver and kidney as well as their cleavage specificity and inhibitors
for them are provided in order to predict enzymatic cleavage of peptide and protein drugs during systemic circulation. |
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Keywords: | : Peptides – Proteins – Plasma half life time – N-C-terminus – PEGylation |
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