Discovery of a class of diketopiperazines as antiprion compounds
| Autor: | Xevi Biarnés, Nieves Cabezas, Pilar López-Alvarado, Alberto López-Cobeñas, Maria Caramelli, Salvatore Bongarzone, J. Carlos Menéndez, Giuseppe Legname, Matteo Staderini, Hoang Ngoc Ai Tran, Paolo Carloni, Maria Laura Bolognesi, Alessandra Monaco |
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| Přispěvatelé: | Bolognesi ML, Tran HNA, Staderini M, Monaco A, Lopez-Cobenas A, Bongarzone S, Biarnes X, Lopez-Alvarado P, Cabezas N, Caramelli M, Carloni P, Menendez JC, Legname G |
| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Molecular model drug design fibrillation inhibitors Prions animal diseases Drug Evaluation Preclinical Computational biology Diketopiperazines Biology Biochemistry Cell Line Prion Diseases Small Molecule Libraries Molecular level Drug Discovery Humans General Pharmacology Toxicology and Pharmaceutics Prion protein Cytotoxicity Pharmacology computational chemistry Prion diseases Organic Chemistry Virology Recombinant Proteins nervous system diseases Molecular Medicine |
| Zdroj: | ChemMedChem. 5(8) |
| ISSN: | 1860-7187 |
| Popis: | 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 (PrP Sc )-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. |
| Databáze: | OpenAIRE |
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