Carbohydrate-based peptidomimetics targeting neuropilin-1: synthesis, molecular docking study and in vitro biological activities

Mylène Richard (1) , Alicia Chateau (2) , Christian Jelsch (3) , Claude Didierjean (3) , Xavier Manival (4) , Christophe Charron (4) , Bernard Maigret (5) , Muriel Barberi-Heyob (2) , Yves Chapleur (1) , Cédric Boura (2) , Nadia Pellegrini-Moise (1)

1 SRSMC - Structure et Réactivité des Systèmes Moléculaires Complexes
2 CRAN - Centre de Recherche en Automatique de Nancy
3 CRM2 - Cristallographie, Résonance Magnétique et Modélisations
4 IMoPA - Ingénierie Moléculaire et Physiopathologie Articulaire
5 CAPSID - Computational Algorithms for Protein Structures and Interactions

Neuropilin-1 (NRP-1), a transmembrane glycoprotein acting as a co-receptor of VEGF-A, is expressed by cancer and angiogenic endothelial cells and is involved in the angiogenesis process. Taking advantage of functionalities and stereodiversities of sugar derivatives, the design and the synthesis of carbohydrate based peptidomimetics are here described. One of these compounds (56) demonstrated inhibition of VEGF-A165 binding to NRP-1 (IC50 = 39 μM) and specificity for NRP-1 over VEGF-R2. Biological evaluations were performed on human umbilical vein endothelial cells (HUVECs) through activation of downstream proteins (AKT and ERK phosphorylation), viability/proliferation assays and in vitro measurements of anti-angiogenic abilities.

Mots clés: Neuropilin-1; VEGF; Carbohydrate scaffolds; Peptidomimetics; Molecular modeling

Domaines: Cancer

Mylène Richard, Alicia Chateau, Christian Jelsch, Claude Didierjean, Xavier Manival, et al.. Carbohydrate-based peptidomimetics targeting neuropilin-1: synthesis, molecular docking study and in vitro biological activities. Bioorganic and Medicinal Chemistry, 2016, 24 (21), pp.5315-5325. ⟨10.1016/j.bmc.2016.08.052⟩. ⟨hal-02356229⟩