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Backbone modification of a polypeptide drug alters duration of action in vivo

Nature Biotechnology volume 32, pages 653–655 (2014)Cite this article

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Abstract

Systematic modification of the backbone of bioactive polypeptides through β-amino acid residue incorporation could provide a strategy for generating molecules with improved drug properties, but such alterations can result in lower receptor affinity and potency. Using an agonist of parathyroid hormone receptor-1 (PTHR1), a G protein–coupled receptor in the B-family, we present an approach for α→β residue replacement that enables both high activity and improved pharmacokinetic properties in vivo.

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Figure 1: Backbone-modified analogs of PTH(1-34) are active in vivo and display improved pharmacokinetic properties.

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Acknowledgements

This research was supported by the US National Institutes of Health (GM056414 (to S.H.G.) and NIDDK-11794 (to T.J.G.)). R.W.C. was supported in part by a National Institutes of Health Biotechnology Training grant (T32 GM008349).

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Authors and Affiliations

  1. Department of Chemistry, University of Wisconsin, Madison, Wisconsin, USA

    Ross W Cheloha & Samuel H Gellman

  2. Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Akira Maeda, Thomas Dean & Thomas J Gardella

Authors
  1. Ross W Cheloha
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  2. Akira Maeda
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  3. Thomas Dean
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  4. Thomas J Gardella
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  5. Samuel H Gellman
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Contributions

R.W.C. and S.H.G. developed the underlying molecular designs, all authors participated in the design and execution of experiments to assess new compounds, and all contributed to data interpretation. S.H.G. and R.W.C. wrote the paper with input from all other authors.

Corresponding authors

Correspondence to Thomas J Gardella or Samuel H Gellman.

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Competing interests

S.H.G. is a co-founder of Longevity Biotech, Inc., which is pursuing biomedical applications of α/β-peptides. S.H.G., R.W.C. and T.J.G. are co-inventors on a patent application covering the PTH analogs described here.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8, Supplementary Tables 1–4, and Supplementary Notes 1 and 2 (PDF 2214 kb)

Supplementary Data File 1

hPTHR1 cAMP Dose Response (XLSX 33 kb)

Supplementary Data File 2

PTH analog induced calcemic response (XLSX 49 kb)

Supplementary Data File 3

PTH analog pharmacokinetic profile data (XLSX 51 kb)

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Cheloha, R., Maeda, A., Dean, T. et al. Backbone modification of a polypeptide drug alters duration of action in vivo. Nat Biotechnol 32, 653–655 (2014). https://doi.org/10.1038/nbt.2920

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