Prospects of PASylation® for the design of protein and peptide therapeutics with extended half-life and enhanced action

Publication date: Available online 15 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Michaela Gebauer, Arne Skerra
Pharmacokinetic (PK) extension is no longer just a means to create improved second generation biologics (so-called biobetters), but constitutes an accepted strategy for biopharmaceutical drug development today. Although PEGylation has become a widely accepted methodology to furnish therapeutic proteins and peptides with prolonged plasma half-life, the immunogenicity and missing biodegradablity of this synthetic polymer has prompted an evident need for alternatives. PASylation is based on biological polypeptides made of the small L-amino acids Pro, Ala and/or Ser (PAS), which adopt a random coil structure in aqueous buffers with surprisingly similar biophysical properties as PEG. In contrast, PAS sequences can be conjugated to pharmaceutically active proteins and peptides both via chemical coupling and at the genetic level, as so-called fusion proteins. PASylation has been successfully applied to numerous biologics, including cytokines, growth factors, antibody fragments, enzymes as well as various peptides, and validated in diverse animal models, from mice to monkeys. Here we compare PASylation with other current strategies for half-life extension and we discuss the utility of these approaches for the design of innovative peptide-based therapeutics.

Graphical abstract

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