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

Publication ,  Journal Article
Banskota, S; Yousefpour, P; Kirmani, N; Li, X; Chilkoti, A
Published in: Biomaterials
February 2019

The clinical utility of many peptide and protein drugs is limited by their short in-vivo half-life. To address this limitation, we report a new class of polypeptide-based materials that have a long plasma circulation time. The design of these polypeptides is motivated by the hypothesis that incorporating a zwitterionic sequence, within an intrinsically disordered polypeptide motif, would impart "stealth" behavior to the polypeptide and increase its plasma residence time, a behavior akin to that of synthetic stealth polymers. We designed these zwitterionic polypeptides (ZIPPs) with a repetitive (VPX1X2G)n motif, where X1 and X2 are cationic and anionic amino acids, respectively, and n is the number of repeats. To test this hypothesis, we synthesized a set of ZIPPs with different pairs of cationic and anionic residues with varied chain length. We show that a combination of lysine and glutamic acid in the ZIPP confer superior pharmacokinetics, for both intravenous and subcutaneous administration, compared to uncharged control polypeptides. Finally, to demonstrate their clinical utility, we fused the best performing ZIPP sequence to glucagon-like peptide-1 (GLP1), a peptide drug used for treatment of type-2 diabetes and show that the ZIPP-GLP1 fusion outperforms an uncharged polypeptide of the same molecular weight in a mouse model of type-2 diabetes.

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Published In

Biomaterials

DOI

EISSN

1878-5905

ISSN

0142-9612

Publication Date

February 2019

Volume

192

Start / End Page

475 / 485

Related Subject Headings

  • Tissue Distribution
  • Peptides
  • Mice, Inbred C57BL
  • Male
  • Intrinsically Disordered Proteins
  • Glucagon-Like Peptide 1
  • Elastin
  • Drug Delivery Systems
  • Diabetes Mellitus, Type 2
  • Diabetes Mellitus, Experimental
 

Citation

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Banskota, S., Yousefpour, P., Kirmani, N., Li, X., & Chilkoti, A. (2019). Long circulating genetically encoded intrinsically disordered zwitterionic polypeptides for drug delivery. Biomaterials, 192, 475–485. https://doi.org/10.1016/j.biomaterials.2018.11.012
Banskota, Samagya, Parisa Yousefpour, Nadia Kirmani, Xinghai Li, and Ashutosh Chilkoti. “Long circulating genetically encoded intrinsically disordered zwitterionic polypeptides for drug delivery.Biomaterials 192 (February 2019): 475–85. https://doi.org/10.1016/j.biomaterials.2018.11.012.
Banskota S, Yousefpour P, Kirmani N, Li X, Chilkoti A. Long circulating genetically encoded intrinsically disordered zwitterionic polypeptides for drug delivery. Biomaterials. 2019 Feb;192:475–85.
Banskota, Samagya, et al. “Long circulating genetically encoded intrinsically disordered zwitterionic polypeptides for drug delivery.Biomaterials, vol. 192, Feb. 2019, pp. 475–85. Epmc, doi:10.1016/j.biomaterials.2018.11.012.
Banskota S, Yousefpour P, Kirmani N, Li X, Chilkoti A. Long circulating genetically encoded intrinsically disordered zwitterionic polypeptides for drug delivery. Biomaterials. 2019 Feb;192:475–485.
Journal cover image

Published In

Biomaterials

DOI

EISSN

1878-5905

ISSN

0142-9612

Publication Date

February 2019

Volume

192

Start / End Page

475 / 485

Related Subject Headings

  • Tissue Distribution
  • Peptides
  • Mice, Inbred C57BL
  • Male
  • Intrinsically Disordered Proteins
  • Glucagon-Like Peptide 1
  • Elastin
  • Drug Delivery Systems
  • Diabetes Mellitus, Type 2
  • Diabetes Mellitus, Experimental