Chemical Optimization of New Ligands of the Low-Density Lipoprotein Receptor as Potential Vectors for Central Nervous System Targeting

被引：65

作者：

Malcor, Jean-Daniel ^{[1
,2
]}

Payrot, Nadine ^{[1
,2
,3
]}

David, Marion ^{[3
]}

Faucon, Aude ^{[3
]}

Abouzid, Karima ^{[3
]}

Jacquot, Guillaume ^{[3
]}

Floquet, Nicolas ^{[1
,2
]}

Debarbieux, Franck ^{[4
,5
]}

Rougon, Genevieve ^{[4
,5
]}

Martinez, Jean ^{[1
,2
]}

Khrestchatisky, Michel ^{[6
,7
]}

Vlieghe, Patrick ^{[3
]}

Lisowski, Vincent ^{[1
,2
]}

机构：

[1] Univ Montpellier I, Inst Biomol Max Mousseron, CNRS UMR5247, UFR Sci Pharmaceut & Biol, F-34093 Montpellier 5, France

[2] Univ Montpellier 2, Inst Biomol Max Mousseron, CNRS UMR5247, UFR Sci Pharmaceut & Biol, F-34093 Montpellier 5, France

[3] VECT HORUS SAS, Fac Med Secteur Nord, CS80011, F-13344 Marseille 15, France

[4] Aix Marseille Univ, UMR6216, Inst Biol Dev Marseille Luminy, F-13288 Marseille 9, France

[5] CNRS, UMR6216, Inst Biol Dev Marseille Luminy, F-13288 Marseille 9, France

[6] Aix Marseille Univ, UMR7259, Lab NICN, Fac Med Secteur Nord, F-13344 Marseille 15, France

[7] CNRS, UMR7259, Lab NICN, Fac Med Secteur Nord, F-13344 Marseille 15, France

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 05期

关键词：

BLOOD-BRAIN-BARRIER; BOND PSEUDOPEPTIDE ANALOGS; RESEARCH-AND-DEVELOPMENT; DRUG-DELIVERY; PEPTIDE-BOND; BIOLOGICAL-ACTIVITIES; DICARBA ANALOGS; IN-VIVO; LDL; PRODUCTIVITY;

D O I：

10.1021/jm2014919

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Drug delivery to the central nervous system is hindered by the presence of physiological barriers such as the blood-brain barrier. To accomplish the task of nutrient transport, the brain endothelium is endowed with various transport systems, induding receptor-mediated transcytosis (RMT). This system can be used to shuttle therapeutics into the central nervous system (CNS) in a noninvasive manner. Therefore, the low-density lipoprotein receptor (LDLR) is a relevant target for delivering drugs. From an initial phage display biopanning a series of peptide ligands for the LDLR was optimized leading to size reduction and improved receptor binding affinity with the identification of peptide 22 and its analogues. Further real-time biphoton microscopy experiments on living mice demonstrated the ability of peptide 22 to efficiently and quickly cross CNS physiological barriers. This validation of peptide 22 led us to explore its binding on the extracellular LDLR domain from an NMR-oriented structural study and docking experiments.

引用

页码：2227 / 2241

页数：15

共 61 条

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