Synthesis and Pharmacological Characterization of Visabron, a Backbone Cyclic Peptide Dual Antagonist of α4β1 (VLA-4)/α9β1 Integrin for Therapy of Multiple Sclerosis

Chaim Gilon, Michal Klazas, Adi Lahiani, Adi Schumacher-Klinger, Shira Merzbach, Johnny N. Naoum, Haim Ovadia, Limor Rubin, Susan Cornell-Kennon, Erik M. Schaefer, Jehoshua Katzhendler, Cezary Marcinkiewicz, Amnon Hoffman, Philip Lazarovici*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Integrins α4β1/ α9β1 are important in the pathogenesis and progression of inflammatory and autoimmune diseases by their roles in leukocyte activation and trafficking. Natalizumab, a monoclonal antibody selectively targeting α4β1 integrin and blocking leukocyte trafficking to the central nervous system, is an immunotherapy for multiple sclerosis (MS). However, due to its adverse effects associated with chronic treatment, alternative strategies using small peptide mimetic inhibitors are being sought. In the present study, we synthesized and characterized visabron c (4-4), a backbone cyclic octapeptide based on the sequence TMLD, a non-RGD unique α4β1 integrin recognition sequence motif derived from visabres, a proteinous disintegrin from the viper venom. Visabron c (4-4) was selected from a minilibrary with conformational diversity based on its potency and selectivity in functional adhesion cellular assays. Visabron c (4-4)'s serum stability, pharmacokinetics, and therapeutic effects following ip injection were assessed in an experimental autoimmune encephalomyelitis (EAE) animal model. Furthermore, visabron c (4-4)'s lack of toxic effects in mice was verified by blood analysis, tissue pathology, immunogenicity, and "off-target"effects, indicating its significant tolerability and lack of immunogenicity. Visabron c (4-4) can be delivered systemically. The in vitro and in vivo data justify visabron c (4-4) as a safe alternative peptidomimetic lead compound/drug to monoclonal anti-α4 integrin antibodies, steroids, and other immunosuppressant drugs. Moreover, visabron c (4-4) design may pave the way for developing new therapies for a variety of other inflammatory and/or autoimmune diseases.

Original languageAmerican English
Pages (from-to)2361-2376
Number of pages16
JournalJACS Au
Volume1
Issue number12
DOIs
StatePublished - 27 Dec 2021

Bibliographical note

Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.

Keywords

  • EAE mice model
  • backbone cyclic TMLD peptide
  • disintegrin
  • immunogenicity
  • integrin-overexpressor cells
  • lymphocytes
  • macrophage
  • multiple sclerosis
  • natalizumab
  • off-target
  • pharmacokinetics
  • safety
  • selectivity
  • serum stability
  • solid-phase peptide synthesis
  • α4β1
  • α9β1

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