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. 2016 Jan 11;55(2):572-5.
doi: 10.1002/anie.201508445. Epub 2015 Oct 23.

MiniAp-4: A Venom-Inspired Peptidomimetic for Brain Delivery

Benjamí Oller-Salvia  1 , Macarena Sánchez-Navarro  1 , Sonia Ciudad  1 , Marc Guiu  1 , Pol Arranz-Gibert  1 , Cristina Garcia  1 , Roger R Gomis  1   2 , Roméo Cecchelli  3 , Jesús García  1 , Ernest Giralt  4   5 , Meritxell Teixidó  6
Affiliations

MiniAp-4: A Venom-Inspired Peptidomimetic for Brain Delivery

Benjamí Oller-Salvia et al. Angew Chem Int Ed Engl. .

Abstract

Drug delivery across the blood-brain barrier (BBB) is a formidable challenge for therapies targeting the central nervous system. Although BBB shuttle peptides enhance transport into the brain non-invasively, their application is partly limited by lability to proteases. The present study proposes the use of cyclic peptides derived from venoms as an affordable way to circumvent this drawback. Apamin, a neurotoxin from bee venom, was minimized by reducing its complexity, toxicity, and immunogenicity, while preserving brain targeting, active transport, and protease resistance. Among the analogues designed, the monocyclic lactam-bridged peptidomimetic MiniAp-4 was the most permeable. This molecule is capable of translocating proteins and nanoparticles in a human-cell-based BBB model. Furthermore, MiniAp-4 can efficiently deliver a cargo across the BBB into the brain parenchyma of mice.

Keywords: apamin; blood-brain barrier; drug delivery; peptides.

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Figures

Figure 1
Figure 1
Comparison of mini‐apamin shuttle candidates. a) Peptide sequences. The disulfides are depicted in yellow and the lactam bridge in orange. b) Relative transport of peptides in the bovine‐cell‐based model. c) Stability of the peptides in human serum. d) Molecular representation of MiniAp‐4, showing the equilibrium between the trans and cis Ala–Pro conformations. e) CD spectra. f) The three lowest‐energy NMR structures of MiniAp‐1. g) Amide regions of the 1H NMR spectra of MiniAp‐2, MiniAp‐3, and MiniAp‐4. The amide resonances of the trans (purple) and cis (pink) conformers are labeled. h) Comparison of the 13Cα chemical shift values of the linear derivative (MiniAp‐2) and the trans (top) and cis (bottom) conformers of the cyclic analogues (MiniAp‐3 and MiniAp‐4). In Figure 1 b and c, error bars represent the standard error of the mean (SEM; n=3, *p<0.05, **p<0.01, ***p<0.001).
Figure 2
Figure 2
IgG titrations. a) Absorbance in the ELISA plate versus serum dilution. b) Antibody titer reported as −log (EC50). n=4 for apamin and MiniAp‐4, n=2 for MiniAp‐1. Error bars represent the standard deviation.
Figure 3
Figure 3
MiniAp‐4 as a new BBB shuttle. a) Protein and NP shuttle conjugates. b) Permeability enhancements that are due to MiniAp‐4 in the human‐cell‐based BBB model. c) Fluorescence intensity of the brain region measured in vivo. d) Fluorescence intensity of various organs ex vivo. e) Representative confocal microscopy images of brain slices (cortex) of mice injected with Cy5.5–MiniAp‐4 (top) and Cy5.5–CA (bottom). The Cy5.5 conjugates are shown in green, capillaries in red, and cell nuclei in blue. Scale bars: 10 μm. Error bars represent the SEM (n=3, *p<0.05, **p<0.01, ***p<0.001). ++ indicates the quantification limit.
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