Discovery of a Class of Diketopiperazines as Antiprion Compounds

被引：52

作者：

Bolognesi, Maria Laura ^{[1
]}

Tran, Hoang Ngoc Ai ^{[2
]}

Staderini, Matteo ^{[3
]}

Monaco, Alessandro ^{[3
]}

Lopez-Cobenas, Alberto ^{[3
]}

Bongarzone, Salvatore ^{[4
,5
]}

Biarnes, Xevi ^{[4
,5
]}

Lopez-Alvarado, Pilar ^{[3
]}

Cabezas, Nieves ^{[3
]}

Caramelli, Maria ^{[6
]}

Carloni, Paolo ^{[4
,5
,7
]}

Carlos Menendez, J. ^{[3
]}

Legname, Giuseppe ^{[2
,5
]}

机构：

[1] Univ Bologna, Dept Pharmaceut Sci, I-40126 Bologna, Italy

[2] Scuola Int Super Studi Avanzati, Scuola Int Super Studi Avanzati, Neurobiol Sector, Lab Prion Biol, I-34151 Trieste, Italy

[3] Univ Madrid, Dept Quim Organ & Farmaceut, Madrid, Spain

[4] Scuola Int Super Studi Avanzati, Scuola Int Super Studi Avanzati, Stat & Biol Phys Sector, I-34151 Trieste, Italy

[5] Italian Inst Technol, SISSA Unit, I-34151 Trieste, Italy

[6] Ist Zooprofilatt Sperimentale Torino, I-10154 Turin, Italy

[7] Rhein Westfal TH Aachen, Forschungzentrum Julich GmbH, German Res Sch Simulat Sci GmbH, Aachen, Germany

来源：

CHEMMEDCHEM | 2010年 / 5卷 / 08期

关键词：

computational chemistry; drug design; fibrillation inhibitors; Prion diseases; PRION PROTEIN; QUINOLINE DERIVATIVES; ALZHEIMERS-DISEASE; POTENT INHIBITION; IN-VITRO; AGGREGATION; DESIGN; BRAIN; THERAPEUTICS; ACCUMULATION;

D O I：

10.1002/cmdc.201000133

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

Prion diseases are fatal neurodegenerative and infectious disorders for which effective pharmacological tools are not yet available. This unmet challenge and the recently proposed interplay between prion diseases and Alzheimer's have led to a more urgent demand for new antiprion agents. Herein, we report the identification of a novel bifunctional diketopiperazine (DKP) derivative 1 d, which exhibits activity in the low micromolar range against prion replication in ScGT1 cells, while showing low cytotoxicity. Supported by properly addressed molecular modeling studies, we hypothesized that a planar conformation is the major determinant for activity in this class of compounds. Moreover, studies aimed at assessing the mechanism-of-action at the molecular level showed that 1 d might interact directly with recombinant prion protein (recPrP) to prevent its conversion to the pathogenic misfolded prion protein (PrPSc)-like form. This investigation suggests that DKP based antiprion compounds can serve as a promising lead scaffold in developing new drugs to combat prion diseases.

引用

页码：1324 / 1334

页数：11

共 63 条

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Novel Pentameric Thiophene Derivatives for in Vitro and in Vivo Optical Imaging of a Plethora of Protein Aggregates in Cerebral Amyloidoses [J].