Research ArticleChemistry

The activity of sulfono-γ-AApeptide helical foldamers that mimic GLP-1

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Science Advances  15 May 2020:
Vol. 6, no. 20, eaaz4988
DOI: 10.1126/sciadv.aaz4988
  • Fig. 1 Chemical and crystal structure of sulfono-γ-AApeptides.

    (A) The chemical structure of sulfono-γ-AApeptides. a and b denote the chiral side chain and the sulfonamido side chain from the building block, respectively. (B) The crystal structure of a sulfono-γ-AApeptide; the cartoon structure was drawn by PyMoL. (C) Top view of (B). (D and E) Schematic representation of distribution of side chains from sulfono-γ-AApeptides. (D) Side view. (E) Top view, helical wheel.

  • Fig. 2 Structural analysis.

    (A) GLP-1 binds to GLP-1R (Protein Data Bank: 5VAI). GLP-1 (7-36) is shown in blue and GLP-1R is represented in green cartoon. (B) The helical domain of GLP-1 with critical residues showing as sticks. (C) Design of sulfono-γ-AApeptide 3, with side chains mimicking the important residues in B. (The helix was built on the crystal structure shown in Fig. 1. X, Y, and Z were designated to indicate the face of residues on the helix, respectively.)

  • Fig. 3 The agonist activities of GLP-1 (7-36) 1, its acylated version 2, and sulfono-γ-AApeptides in the activation of GLP-1R using the cell-based HTRF assay.

  • Fig. 4 CD spectra of regular GLP-1 peptides 1 and 2 and sulfono-γ-AApeptides 3 to 16 (100 μM) measured in phosphate-buffered saline buffer.

  • Fig. 5 Stability study and oral glucose tolerance test.

    (A) Analytic HPLC traces of 1, 2, 3, and 5 before and after incubation with Pronase (0.1 mg/ml). (B) The serum stability of 1, 2, 3, and 5 was determined in 25% serum (v/v) at 37°C for 24 hours. (C and D) Pharmacodynamics of the GLP-1 mimic peptides in mice. A Single dose of peptides was intraperitoneally administered into mice 1 hour before the oral glucose tolerance test (OGTT) (2 g/kg glucose). (C) Blood glucose concentrations were monitored for up to 120 min after oral glucose challenge. (D) Average area under the curve (AUC) calculated from OGTT data. Results show mean ± SEM of six mice per treatment group; *P < 0.05 versus vehicle; t test.

  • Table 1 Structures of GLP-1(7-36) 1 and 2 and sulfono-γ-AApeptides 3 to 16.
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Supplementary Materials

  • Supplementary Materials

    The activity of sulfono-γ-AApeptide helical foldamers that mimic GLP-1

    Peng Sang, Zhihong Zhou, Yan Shi, Candy Lee, Zaid Amso, David Huang, Timothy Odom, Vân T.B. Nguyen-Tran, Weijun Shen, Jianfeng Cai

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