Parallel solid-phase synthesis of a small library of linear and hydrocarbon-bridged analogues of VEGF_81–91: Potential biological tools for studying the VEGF/VEGFR-1 interaction

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• 作者：Mar&#xed ; a Isabel Garc&#xed ; a-Aranda^a ; Patricia Marrero^a ; Benoit Gautier^b ; Mercedes Mart&#xed ; n-Mart&#xed ; nez^a ; Nicolas Inguimbert^b ; ^† ; ; Michel Vidal^b ; ^‡ ; ; Mar&#xed ; a Teresa Garc&#xed ; a-Ló ; pez^a ; Mar&#xed ; a Angeles Jim&#xe9 ; nez^c ; Rosario Gonz&#xe1 ; lez-Muñ ; iz^a ; Mar&#xed ; a Jesú ; s P&#xe9 ; rez de Vega^a ; ^{pdevega@iqm.csic.es}
• 关键词：VEGF ; Peptides ; Ring-closing-metathesis ; Solid-phase synthesis ; Protein– ; protein interactions ; Angiogenesis
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2011
• 出版时间：15 March 2011
• 年：2011
• 卷：19
• 期：6
• 页码：1978-1986
• 全文大小：604 K

文摘

The design, synthesis and binding affinity for VEGFR-1 receptors of a small library of linear and cyclic analogues of the VEGF_81–91 fragment are described. Cyclic 11- and 10-mer peptide derivatives were prepared using parallel solid-phase protocols. The formation of hydrocarbon alkene-bridged cyclic peptides was achieved through optimized ring-closing metathesis reactions from linear derivatives with conveniently located allylGly residues. Alkane-bridged analogues were successfully obtained by ulterior on-resin hydrogenation. Binding assays showed that some of these compounds were able to compete with labeled VEGF for interaction with the VEGFR-1 receptor. Several peptide derivatives, 2, 7 and 8, showed modest but significant binding affinity, indicating that the designed peptide could mimic the VEGF_81–91 fragment and therefore disrupt the VEGF/VEGFR-1 interaction. This fact opens the way for using these peptides as the starting point for biological/pharmacological tools to deeply investigate this protein–protein system.