Strategies to improve plasma half life time of peptide and protein drugs

Abstract

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 PEG(2,40 K) conjugate of INF-alpha-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.

Combination therapy of an anticancer drug with the FNIII14 peptide of fibronectin effectively overcomes cell adhesion-mediated drug resistance of acute myelogenous leukemia

“…Furthermore, FNIII14 may also be effective for treating those malignancies in which CAM-DR is mediated by b1-integrins other than VLA-4, such as VLA-5. 45,16 On the other hand, the plausible disadvantage of peptide preparation is its relatively shorter half-life in circulation 46 than protein preparations. 47 However, this problem may be conquered by modification of the peptide with polyethyleneglycol conjugation, 48 protease modification 49 or hydrocarbon stapling.…”

UPARANT: A Urokinase Receptor–Derived Peptide Inhibitor of VEGF-Driven Angiogenesis with Enhanced Stability and In Vitro and In Vivo Potency

“…We synthesized new peptides containing a-methyl-a-amino acids, and they were characterized from a biologic point of view. All these new analogues are N-acetylated and C-amidated, as being a common way of the N-and C-terminal modifications to enhance the stability to exopeptidasemediated proteolysis (21). Among the new series of peptides, Ac-L-Arg-Aib-L-Arg-D-Ca(Me)Phe-NH 2 , showed the best desired activity in preliminary experiments of VEGF-directed endothelial cell migration.…”

Intravenous Administration of Polyethylene Glycol-Coated (PEGylated) Proteins and PEGylated Adenovirus Elicits an Anti-PEG Immunoglobulin M Response

“…Biomedicines, such as protein drugs 1,2) and nucleic acid drugs, 3) have attracted considerable attention due to their high biological activity and specificity against target molecules. However, their application is sometimes limited due to their insufficient clinical effects as a result of susceptibility to destruction by proteolytic or nucleolytic enzymes, a short circulating half-life, low solubility, rapid kidney clearance and propensity to generate neutralizing antibodies.…”

“…4) Covalent conjugation of polyethylene glycol (PEG) to the biological active molecules, by a process called "PEGylation," is one of the promising strategies being used to overcome these limitations. [1][2][3] PEG is one of the most versatile synthetic polymers and is widely believed to lack immunogenicity and toxicity and shows high solubility in water and in many organic solvents. 4,5) For instance, proteins modified with PEG have an increased solubility due to the hydrophilicity of grafted PEG; their destruction by protease and the immune system is decreased due to the steric hindrance of grafted PEG; and, glomerular filtration is decreased due to an increase in the apparent size or hydrodynamic volume of a given protein.…”