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Multivalency Increases the Binding Strength of RGD Peptidomimetic‐Paclitaxel Conjugates to Integrin α V β 3
Author(s) -
Raposo Moreira Dias André,
Pina Arianna,
Dal Corso Alberto,
Arosio Daniela,
Belvisi Laura,
Pignataro Luca,
Caruso Michele,
Gennari Cesare
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201703093
Subject(s) - peptidomimetic , conjugate , integrin , linker , chemistry , dipeptide , ligand (biochemistry) , monomer , stereochemistry , combinatorial chemistry , paclitaxel , moiety , pegylation , biophysics , peptide , receptor , biochemistry , polymer , biology , organic chemistry , chemotherapy , mathematical analysis , mathematics , computer science , genetics , operating system , polyethylene glycol
This work reports the synthesis of three multimeric RGD peptidomimetic‐paclitaxel conjugates featuring a number of α V β 3 integrin ligands ranging from 2 to 4. These constructs were assembled by conjugation of the integrin α V β 3 ligand cyclo [DKP‐RGD]‐CH 2 NH 2 with paclitaxel via a 2′‐carbamate with a self‐immolative spacer, the lysosomally cleavable Val‐Ala dipeptide linker, a multimeric scaffold, a triazole linkage, and finally a PEG spacer. Two monomeric conjugates were also synthesized as reference compounds. Remarkably, the new multimeric conjugates showed a binding affinity for the purified integrin α V β 3 receptor that increased with the number of integrin ligands (reaching a minimum IC 50 value of 1.2 n m for the trimeric), thus demonstrating that multivalency is an effective strategy to strengthen the ligand–target interactions.