Manzoni Leonardo, Belvisi Laura, Arosio Daniela, Civera Monica, Pilkington-Miksa Michael, Potenza Donatella, Caprini Andrea, Araldi Elena M V, Monferini Eugenia, Mancino Monica, Podestà Francesca, Scolastico Carlo
Istituto di Scienze e Tecnologie Molecolari, Consiglio Nazionale delle Ricerche, Milano, Italy.
ChemMedChem. 2009 Apr;4(4):615-32. doi: 10.1002/cmdc.200800422.
Cyclic RGD-containing functionalized azabicycloalkane peptides were synthesized with the aim of developing high-affinity selective integrin ligands as carriers for therapeutic and diagnostic purposes. Herein we describe the synthesis and in vitro screening of these RGD derivatives, as well as the determination of their conformational properties in solution by spectroscopic and computational methods. Docking studies with the X-ray crystal structure of the extracellular domain of integrin alpha(v)beta(3) were also performed to elucidate the structural binding requirements and to rationalize the biological results. One compound in particular was found to be the best alpha(v)beta(3) integrin binder (IC(50)=53.7 nM) among the new functionalized RGD cyclic peptides, thus emerging as a promising candidate for covalent bonding and selective homing of useful functional units.
合成了含环状RGD的功能化氮杂双环烷肽，目的是开发高亲和力的选择性整合素配体，作为治疗和诊断用途的载体。本文描述了这些RGD衍生物的合成和体外筛选，以及通过光谱和计算方法测定它们在溶液中的构象性质。还进行了与整合素α(v)β(3)细胞外结构域的X射线晶体结构的对接研究，以阐明结构结合要求并合理化生物学结果。特别发现一种化合物是新的功能化RGD环肽中最好的α(v)β(3)整合素结合剂(IC(50)=53.7 nM)，因此成为有用功能单元共价键合和选择性归巢的有前途的候选物。
