Characterizing antiprion compounds based on their binding properties to prion proteins: implications as medical chaperones.
A variety of antiprion compounds have been reported that are effective in ex vivo and in vivo treatment experiments. However, the molecular mechanisms for most of these compounds remain unknown. Here we classified antiprion mechanisms into four categories: I, specific conformational stabilization; II, nonspecific stabilization; III, aggregation; and IV, interaction with molecules other than PrP(C). To characterize antiprion compounds based on this classification, we determined their binding affinities to PrP(C) using surface plasmon resonance and their binding sites on PrP(C) using NMR spectroscopy. GN8 and GJP49 bound specifically to the hot spot in PrP(C), and acted as "medical chaperones" to stabilize the native conformation. Thus, mechanisms I was predominant. In contrast, quinacrine and epigallocathechin bound to PrP(C) rather nonspecifically; these may stabilize the PrP(C) conformation nonspecifically including the interference with the intermolecular interaction following mechanism II. Congo red and pentosan polysulfate bound to PrP(C) and caused aggregation and precipitation of PrP(C), thus reducing the effective concentration of prion protein. Thus, mechanism III was appropriate. Finally, CP-60, an edarabone derivative, did not bind to PrP(C). Thus these were classified into mechanism IV. However, their antiprion activities were not confirmed in the GT + FK system, whose details remain to be elucidated. This proposed antiprion mechanisms of diverse antiprion compounds could help to elucidate their antiprion activities and facilitate effective antiprion drug discovery.
Life Science Research Center, Gifu University, Gifu 501-1194, Japan.
Yuji O
YO
Kamatari
Yosuke
Y
Hayano
Kei-ichi
K
Yamaguchi
Junji
J
Hosokawa-Muto
Kazuo
K
Kuwata
D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000631:Aminopyridines / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology; D002392:Catechin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D003224:Congo Red / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D018832:Molecular Chaperones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology; D010426:Pentosan Sulfuric Polyester / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D011328:Prions / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation / Q000187:drug effects; D011796:Quinacrine / Q000737:chemistry / Q000494:pharmacology; D020349:Surface Plasmon Resonance
C569929:2,3,4,9-tetrahydro-9-(2-hydroxy-3-(1-piperidinyl)propyl)-6-methyl-1H-carbazol-1-one; D000577:Amides; D000631:Aminopyridines; D002227:Carbazoles; C410007:Cp 60 compound; D018832:Molecular Chaperones; D009570:Nitriles; D010880:Piperidines; D011328:Prions; D010426:Pentosan Sulfuric Polyester; D003224:Congo Red; D002392:Catechin; C045651:epigallocatechin gallate; D011796:Quinacrine