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Long circulating genetically encoded intrinsically disordered zwitterionic polypeptides for drug delivery.

Samagya Banskota1, Parisa Yousefpour1, Nadia Kirmani2

  • 1Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA.

Biomaterials
|December 4, 2018
PubMed
Summary

Researchers developed zwitterionic polypeptides (ZIPPs) to extend drug circulation time. ZIPP-fused GLP1 demonstrated improved efficacy in a type-2 diabetes mouse model, offering potential for enhanced peptide therapeutics.

Keywords:
Bioinspired materialsRecombinant proteinsUnstructured polypeptidesZwitterionic polypeptides

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Area of Science:

  • Biomaterials Science
  • Drug Delivery Systems
  • Protein Engineering

Background:

  • Peptide and protein drugs often have short in-vivo half-lives, limiting their clinical application.
  • Developing strategies to prolong plasma circulation time is crucial for improving therapeutic efficacy.
  • Existing synthetic stealth polymers offer a model for achieving extended residence times.

Purpose of the Study:

  • To design and synthesize a novel class of zwitterionic polypeptides (ZIPPs) with extended plasma circulation times.
  • To investigate the pharmacokinetic properties of ZIPPs and identify optimal sequences for enhanced drug delivery.
  • To evaluate the therapeutic potential of ZIPP-drug conjugates using a type-2 diabetes model.

Main Methods:

  • Design of repetitive (VPX1X2G)n zwitterionic polypeptide sequences incorporating cationic and anionic amino acids.
  • Synthesis and characterization of various ZIPP constructs with differing amino acid pairs and chain lengths.
  • Pharmacokinetic studies in vivo following intravenous and subcutaneous administration, and in vivo efficacy testing of a ZIPP-GLP1 fusion in a type-2 diabetes mouse model.

Main Results:

  • Zwitterionic polypeptides (ZIPPs) demonstrated significantly longer plasma circulation times compared to uncharged control polypeptides.
  • A specific ZIPP sequence incorporating lysine and glutamic acid exhibited superior pharmacokinetic profiles.
  • The ZIPP-GLP1 fusion protein showed enhanced therapeutic efficacy in a mouse model of type-2 diabetes compared to an equivalent uncharged polypeptide.

Conclusions:

  • Zwitterionic polypeptides represent a promising new class of biomaterials for extending the in-vivo half-life of therapeutic proteins and peptides.
  • The developed ZIPP technology offers a viable strategy for improving the pharmacokinetic and pharmacodynamic properties of peptide-based drugs.
  • ZIPP-drug conjugates hold significant potential for advancing the treatment of diseases like type-2 diabetes.