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Introduction of Chemical Modifications-Based Half-Life Extension

Chemical modification of peptides and proteins has become an essential route to enhance the PK profile of biopharmaceuticals. Herein we provide an overview of some important chemical modifications to provide half-life extension of biopharmaceuticals, which are alternatives to PEGylation. The emphasis is on chemical moieties, the biophysical properties they direct, and their biological compatibility. One approach to improve the pharmacokinetic properties of peptides relies on chemical moieties that convey protraction by binding to albumin and promote self-assembly to form larger structures. Biopharmaceuticals modified to bind to albumin have an extended mode of action, which in principle can approach the 19-days half-life of albumin. Alternative strategies to improve PK properties rely on covalent conjugation or fusion to long-lived macromolecules with low immunogenicity.

Fig.1 Half-Life Extension of Biopharmaceuticals using Chemical Methods. (van Witteloostuijn, 2016)

Methods based on chemical modifications for half-life extension

• Lipidation Based Half-life Extension Service
  Lipidation of peptides and proteins is a well-known and important posttranslational modification, with examples including S-prenylation, N-myristoylation, S-palmitoylation, N-palmitoylation, O-octanoylation, and cholesteroylation. The mechanism of the first lipidated biopharmaceutical's extended half-life involves both albumin binding and protraction of absorption by oligomerization. Recently, lipidation has also been shown as a viable strategy for the half-life extension of larger proteins.
• Perfluoroalkylation Based Half-Life Extension Service
  Highly fluorinated molecules tend to segregate into a fluorous phase, a phenomenon, which is often referred to as the fluorous effect. Attaching a perfluoroalkyl group on the surface of a protein could potentially direct intermolecular fluorous self-assembly, representing a bio-orthogonal approach to control the oligomeric state of proteins in solution.
• Bipyridyl Based Half-Life Extension Service
  2,2'-bipyridyl (Bipy) has a high affinity for Fe^II and forms a chiral tris-bipy Fe^II complex, which is colored. Bipy was first attached to an insulin variant, insulin X2, which has a low propensity to form the hexamer and is mainly in the monomer/dimer. Next, bipy was anchored to human insulin. This conjugate can lower blood glucose upon i.v. injection. It forms higher-ordered structures, combining native Zn²⁺ complexation with abiotic Fe²⁺ binding. This is a significant step toward the construction of novel peptide and protein drugs, which change their oligomeric state in response to metal ion concentration. While the half-life extension of the two latter strategies was not tested, it can be speculated that they have the potential for this.

Creative Biolabs is a leading biotechnology company. We have been focused on drug development for many years. Our team has senior experts and very rich project experience. We're committed to helping you achieve your goal of half-life extension drug development by chemical modifications. If you have any problems with half-life extension drug development or you are interested in our half-life extension service by chemical modifications, please do not hesitate to contact us for more details.

Reference

1. van Witteloostuijn, S.B.; et al. Half-life extension of biopharmaceuticals using chemical methods: alternatives to PEGylation. ChemMedChem. 2016, 11(22): 2474-2495.

Related Services:

• Lipidation Based Half-life Extension Service
• Perfluoroalkylation Based Half-Life Extension Service
• Bipyridy Based Half-Life Extension Service