Discovery of a class of diketopiperazines as antiprion compounds.
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.
Department of Pharmaceutical Sciences, University of Bologna, Italy. marialaura.bolognesi@unibo.it
Maria Laura
ML
Bolognesi
Hoang Ngoc
HN
Ai Tran
Matteo
M
Staderini
Alessandra
A
Monaco
Alberto
A
López-Cobeñas
Salvatore
S
Bongarzone
Xevi
X
Biarnés
Pilar
P
López-Alvarado
Nieves
N
Cabezas
Maria
M
Caramelli
Paolo
P
Carloni
J Carlos
JC
Menéndez
Giuseppe
G
Legname
D002460:Cell Line; D054659:Diketopiperazines / Q000737:chemistry* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008958:Models, Molecular; D017096:Prion Diseases / Q000188:drug therapy; D011328:Prions / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000627:therapeutic use
D054659:Diketopiperazines; D011328:Prions; D011994:Recombinant Proteins; D054852:Small Molecule Libraries