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.
Bolognesi
Maria Laura
ML
Department of Pharmaceutical Sciences, University of Bologna, Italy. marialaura.bolognesi@unibo.it
Ai Tran
Hoang Ngoc
HN
Staderini
Matteo
M
Monaco
Alessandra
A
López-Cobeñas
Alberto
A
Bongarzone
Salvatore
S
Biarnés
Xevi
X
López-Alvarado
Pilar
P
Cabezas
Nieves
N
Caramelli
Maria
M
Carloni
Paolo
P
Menéndez
J Carlos
JC
Legname
Giuseppe
G
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