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Discovery of a Class of Diketopiperazines as Antiprion Compounds
Author(s) -
Bolognesi Maria Laura,
Ai Tran Hoang Ngoc,
Staderini Matteo,
Monaco Alessandra,
LópezCobeñas Alberto,
Bongarzone Salvatore,
Biarnés Xevi,
LópezAlvarado Pilar,
Cabezas Nieves,
Caramelli Maria,
Carloni Paolo,
Menéndez J. Carlos,
Legname Giuseppe
Publication year - 2010
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201000133
Subject(s) - diketopiperazines , drug discovery , computational biology , prion protein , cytotoxicity , recombinant dna , biology , chemistry , in vitro , bioinformatics , medicine , biochemistry , disease , stereochemistry , gene , pathology
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.