Herein we report the synthesis of three multimeric RGD peptidomimetic-paclitaxel conjugates featuring a number of αVβ3 integrin ligands ranging from 2 to 4 (compounds 7-9). These constructs were assembled by conjugation of the integrin αVβ3 ligand cyclo[DKP-RGD]-CH2NH2 (2) with paclitaxel (3) 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 (compounds 5-6) were also synthesized as reference compounds. Remarkably, the new multimeric conjugates showed a binding affinity for the purified integrin αVβ3 receptor which increased with the number of integrin ligands (reaching a minimum IC50 value of 1.2 nM for the trimeric), thus demonstrating that multivalency is an effective strategy to strengthen the ligand-target interactions.
Multivalency Increases the Binding Strength of RGD Peptidomimetic-Paclitaxel Conjugates to Integrin αVβ3 / A.F. Raposo Moreira Dias, A. Pina, A. Dal Corso, D. Arosio, L. Belvisi, L.L. Pignataro, M. Caruso, C.M.A. Gennari. - In: CHEMISTRY-A EUROPEAN JOURNAL. - ISSN 0947-6539. - 23:58(2017 Oct 17), pp. 14410-14415.
Multivalency Increases the Binding Strength of RGD Peptidomimetic-Paclitaxel Conjugates to Integrin αVβ3
A.F. Raposo Moreira DiasPrimo
;A. PinaSecondo
;A. Dal Corso;L. Belvisi;L.L. Pignataro
;C.M.A. Gennari
Ultimo
2017
Abstract
Herein we report the synthesis of three multimeric RGD peptidomimetic-paclitaxel conjugates featuring a number of αVβ3 integrin ligands ranging from 2 to 4 (compounds 7-9). These constructs were assembled by conjugation of the integrin αVβ3 ligand cyclo[DKP-RGD]-CH2NH2 (2) with paclitaxel (3) 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 (compounds 5-6) were also synthesized as reference compounds. Remarkably, the new multimeric conjugates showed a binding affinity for the purified integrin αVβ3 receptor which increased with the number of integrin ligands (reaching a minimum IC50 value of 1.2 nM for the trimeric), thus demonstrating that multivalency is an effective strategy to strengthen the ligand-target interactions.File | Dimensione | Formato | |
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Raposo-Moreira-Dias_et_al-2017-Chemistry_-_A_European_Journal.pdf
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