Synthesis and Pharmacological Characterization of
Visabron, a Backbone Cyclic Peptide Dual Antagonist of α4β1
(VLA-4)/α9β1 Integrin for Therapy of Multiple Sclerosis
posted on 2021-11-24, 19:46authored byChaim 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
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.