Enhanced Permeability and Binding Activity of Isobutylene-Grafted Peptides

  1. Sun, S. 2
  2. Compañón, I. 1
  3. Martínez-Sáez, N. 2
  4. Seixas, J.D. 3
  5. Boutureira, O. 2
  6. Corzana, F. 1
  7. Bernardes, G.J.L. 23
  1. 1 Universidad de La Rioja
    info

    Universidad de La Rioja

    Logroño, España

    ROR https://ror.org/0553yr311

  2. 2 University of Cambridge
    info

    University of Cambridge

    Cambridge, Reino Unido

    ROR https://ror.org/013meh722

  3. 3 Universidade de Lisboa
    info

    Universidade de Lisboa

    Lisboa, Portugal

    ROR https://ror.org/01c27hj86

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Revista:
Chembiochem : a European journal of chemical biology

ISSN: 1439-4227

Año de publicación: 2018

Volumen: 19

Número: 1

Páginas: 48-52

Tipo: Artículo

DOI: 10.1002/CBIC.201700586 SCOPUS: 2-s2.0-85034768515 WoS: WOS:000419236800008 GOOGLE SCHOLAR

Otras publicaciones en: Chembiochem : a European journal of chemical biology

Repositorio institucional: lock_openAcceso abierto Editor

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Resumen

We present a new peptide-macrocyclization strategy with an isobutylene graft. The reaction is mild and proceeds rapidly and efficiently both for linear and cyclic peptides. The resulting isobutylene-grafted peptides possess improved passive membrane permeability due to the shielding of the polar backbone of the amides, as demonstrated by NMR spectroscopy and molecular dynamics simulations. The isobutylene-stapled structures are fully stable in human plasma and in the presence of glutathione. This strategy can be applied to bioactive cyclic peptides such as somatostatin. Importantly, we found that structural preorganization forced by the isobutylene graft leads to a significant improvement in binding. The combined advantages of directness, selectivity, and smallness could allow application to peptide macrocyclization based on this attachment of the isobutylene graft. © 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.