Table 1.

Anti-prion therapeutics.

Drug	Type	Model	Efficacy	Suggested mechanism	Strain Specificity	References
PrPsc target
Congo Red	Sulfonated amyloid dye	Neuronal cell culture, hamster	Decreases PrPSc accumulation and inhibits propagation in culture, prolongs mean incubation period in vivo	Stabilizes PrPSc, inhibits GAG-PrP binding and potentially PrPC-PrPSc binding	127S, Sc237, PrP (27–30), 263K, 139H	127–131
LIN5001, LIN7002, LIN5044	Luminescent conjugated polythiophenes (LCPs)	Mouse	IV infusion prolongs survival, reduces infectivity	Aggregate hyperstabilization	RML6, 263K	132,133
Compound B	4-pyridinecarboxaldehyde, 2-[4-(5-oxazolyl)phenyl] hydrazone	Neuronal cell culture, mouse	Eliminates PrPSc in culture; prolongs incubation period/life, reduces PrP deposition, large quantity needed for efficacy	Binds to abnormal PrP, inhibits new formation of abnormal PrP	RML, 22L (marginally), Fukuoka-1 GSS, 263K (barely)	134,135
anle138b	3,5-diphenyl-pyrazole (DPP)	Neuronal cell culture, mouse	Antiprion activity in vitro and in vivo, substantial prolongation of survival (txt after clinical onset), good bioavailability, BBB penetration	Directly blocks PrPSc amplification, causes shift towards smaller PrPSc oligomer size, inhibits pathological aggregation (PrPSc specific)	RML, ME7, 301c, sCJD, vCJD, a-syn	136–138
U18666A	Cholesterol synthesis inhibitor	Neuronal cell culture	Significantly decreased PrP-res levels	Redistributes PrPSc to late endosome-lysosome, degradation of PrPSc in secondary lysosomes	22L	139
Pentosan Polysulfate (PPS)	Cysteine protease inhibitor	Neuronal cell culture, mouse, human	IV infusion prolonged survival even when administered after abnormal PrP deposition, rapidly and significantly decreased PrPSc levels, various efficacy in humans	May act as a competitive coreceptor (with endogenous GAG or other proteoglycans) for PrP at cell surface or causes fragmentation of PrPSc at the cell surface	263K, RML, Fukuoka-1 GSS, 22L, iCJD, vCJD	139–147
Heterologous protein	Hamster PrP	Neuronal cell culture, mouse	Decreases PrP-res in culture, slows disease progression, increases survival, significantly delays onset of clinical signs, decreases PrPSc accumulation in brain/spleen	Either binds to PrPSc creating a functionally impotent aggregate unable to produce additional PrPSc or binds and blocks the conversion site from PrPC	RML-Chandler	148–151
IND24, IND81, IND114338, IND125, IND126461	2-aminothiazoles	Neuronal cell culture, mouse	Strain-specific and administration time-dependent extension in survival, decreased & altered distribution of PrPSc in brain, can lead to drug resistance (e.g. IND24-resistant RML)	Inhibits formation of new PrPSc, reduces PrPSc load via drug-like mechanism, might promote clearance of PrPSc	RML, ME7, 22L, CWD	138,152–156
Amphotericin B	Fungizone (polyene antibiotic)	Neuronal cell culture, mouse, hamster, human	Administration time-dependent prolongation of incubation period, delays onset of clinical signs without improvement of neurological symptoms or prolongation of clinical disease, delays accumulation ofPrPSc in the brain	Potentially could: interact with PrPC/PrPSc, interfere with uptake of PrPSc into cells, target detergent-resistant microdomains (modify cell surface distribution and/or trafficking of PrP), regulate microglial/glial activation, directly bind and either “cap” amyloid growth or overstabilize PrPSc	263K, CJD	140,157–164
PrPC Target
771, active ASO 1, active ASO 2	Antisense oligonucleotide	Neuronal cell culture, mouse	Reduces PrPC/PrPSc in cell culture and in vivo, delays onset of clinical signs, slows disease progression, toxicity issues when administered after prion inoculation	Decreased PrPC levels slow accumulation of PrPSc	RML, potentially more since PrPC is the target	165,166
J1, J8, J20, J35	Chalcones	Neuronal cell culture	Decreases PrPSc levels, completely blocks PrP109–149 aggregation	Directly binds to PrPC (C-terminal), decreases amount of PrPC on cell surface (arrest in ER), may stabilize PrPC or bind seeding surface	RML, 22L, CWD, 263K, CJD	167,168
Y13, Y17	Oxadiazole	Neuronal cell culture	Could not totally block conversion but Increased lag phase for conversion; minor decrease in PrP-res formed in RT-QuIC	Direct binding to PrPC (stabilize PrPC or bind at seeding surface), potentially interacts with PrPC/PrPSc N-terminal region, decrease amount of PrPC on cell surface causing arrest in ER	RML, 263K, CJD	167,168
Fe(III)-TMPyP	Cationic tetrapyrrole	Neuronal cell culture, mouse	Inhibits replication in vitro/cell culture, prolongs survival, inhibits amplification of PrPSc, inhibits cytotoxic effects of delta CR PrP	Interacts with C-terminal domain of PrPC (Helix-3), acts as pharmacological chaperone for PrPC (decreases prion-induced misfolding)	RML, 22L, bank vole strains (Italian, UK (SCR1), and CH1641)	169,170
D18	Anti-recombinant PrP (29–231) antibody (residues 132–156; helix A) Fabs	Neuronal cell culture, mouse	Abolishes prion replication and clears existing PrPSc in cell culture (2 week txt), prolongs incubation period and decreased titer in mice	Binds to PrPC on cell surface and hinders docking of PrPSc/a cofactor needed for conversion	Scrapie	171
6H4	Anti-murine PrPC antibody (Mab and expressed as transgene)	Neuronal cell	Prevents infection of susceptible cells, cures chronically infected cultures, conferred anti-PrP titers (Prnp0/0 mice) w/o induction of autoimmune disease, no infectivity detected (Prnp+/0-6H4u mice) when challenged, prevents or drastically delays pathogenesis	Occludes PrPC at prion replication sites, captures and degrades (immune-mediated) incoming PrPSc inoculum, steric competition with template-directed refolding, interference with seeded PrPSc nucleation reaction	RML	172,173
ICSM 18	Isotype IgG1, anti-murine alpha-PrP antibody (residues 146–159)	Neuronal cell culture, mouse	Reduces splenic PrPSc levels, increases survival, passive transfer of Abs had no effect late in incubation period	Direct inhibition of PrPSc production, binding may bury “active residues” and stabilize helix 1	RML	174,175
110	Monoclonal anti-PrP antibody (PHGGGWG at aa 59–65 and aa 83–89; octarepeat region)	Neuronal cell culture	Reduced PrPSc accumulation (dose-dependent) in cell culture, long term txt increased PrPC levels	Retains PrPC on cell surface (may interfere with PrPC metabolism), mAb-PrPC binding inhibits PrPC-PrPSc interaction by occupying binding domain or through steric interference	Chandler (139A), RML	176
6D11	Monoclonal antibody, recognizes PrPC, PrPSc, and recPrP (epitope between 93–109)	Neuronal cell culture	Complete abrogation of PrPSc, no re-emergence for at least 14 days, (following removal of txt), pre-incubation prevents infection	May prevent PrPC-PrPSc interaction or interfere with binding auxiliary molecules needed for prion propagation	22L	177
7H6	Monoclonal Ab, recognizes residues 130–140	Neuronal cell culture	Complete abrogation of PrPSc, no re-emergence for at least 14 days, (following removal of txt)	Similar to 6D11?	22L	177
7A12	Monoclonal Ab, recognizes residues 143–155 (alpha-helix A)	Neuronal cell culture	Complete abrogation of PrPSc, no re-emergence for at least 14 days, (following removal of txt), weakest preventative effect	Similar to 6D11?	22L	177
SAF34	Monoclonal Ab, recognizes residues 59–89 (HuPrP)	Neuronal cell culture	Dose-dependent decrease of PrPSc levels, increased inhibition when used in conjunction with SAF61, re-emergence of PrPSc following removal of txt	Decreases half-life of PrPC, antibodies act on PrPC or PrPSc isoforms, antibodies prevent PrPC-PrPSc interaction	22L	178
SAF61	Monoclonal Ab, recognizes residues 144–152 (HuPrP)	Neuronal cell culture	Dose-dependent decrease of PrPSc levels, increased inhibition of PrPSc when used in conjunction with SAF34, no re-emergence ofPrPSc following removal oftxt	Decreases half-life of PrPC, antibodies act on PrPC or PrPSc isoforms, antibodies prevent PrPC-PrPSc interaction, increase clearance/degradation of PrPC, modulate cellular trafficking of PrP, induce conformational change exposing PrP to protease attacks	22L	178
PrioV3	Camelid anti-PrP antibody (residues between 171 and 190, YYR motif)	Neuronal cell culture, endo-thelial cells, mouse	Crosses BBB in vitro and in vivo, abrogates PrPSc replication in cells, permanent depletion of PrPSc in cells, marked inhibition ofPrPSc accumulation in spleen	Alters PrPC expression (direct neutralizing effect on PrPC/PrPSc), could block PrPC incorporation into infectious PrPSc	RML	179,180
44B1	Monoclonal antibody	Neuronal cell culture	Rapidly and significantly decreased PrPSc levels	Retains PrPC on cell surface as an antigen-antibody complex, interferes with internalization and trafficking of PrPC to endocytic compartments	22L	139
POM2	Anti-PrP antibody to flexible tail of PrPC	Mouse COCS	Prevented prion-mediated neurodegeneration but prion titer was not decreased	Induces shift in distribution ofPrPSc moieties without affecting overall quantity	RML	181
LD7, JZ107	Phenethyl piperidine	Neuronal cell culture	Reduced PrPSc by 50%, permanently cured RML-infected cells (1 month exposure), protects against dendritic spine loss in presence of PrPSc	Might interact with PrPC in a cellular context, perhaps in conjunction with other cell-surface receptors, may interact with PrPC substrate	RML, 22L	182
Alprenolol hydrochloride	B-adrenergic blocker	Neuronal cell culture, mouse	Reduced levels of PrPSc in cells and brains of infected mice, inhibited PrPSc accumulation and spongiform changes but did not prolong survival	May inhibit via interaction with PrPC	Fukuoka-1	183
R12, R24, R12-A-R12	RNA aptamer	Neuronal cell culture	Significantly reduces PrPSc levels in cell culture	Tightly binds to and stabilizes PrPC, blocking conversion to PrPSc	Fukuoka-1	184,185
DE10, DC2, EB8, EF2	Monoclonal antibodies to N-terminal region of PrPSc	Neuronal cell culture	Promoted complete clearance ofPrPSc in cell culture	Binds to a region on PrPC that PrPSc also binds, blocking PrPC-PrPSc interaction	RML	186
PrP C /PrP Sc
Chlorpromazine (CPZ)	Phenothiazine	Neuronal cell culture	No to modest effect on PrPSc accumulation, inhibits prion replication in cells but not in vitro	Decreases PrPC at cell surface by inhibiting clathrin-mediated endocytosis, redistributes PrPSc to late endosome-lysosome	sheep scrapie 127S, Sc237, Type 1 CJD, RML, 22L	129,139,187
Quinacrine	Lysosomotropic agent	Neuronal cell culture, mouse, humans	Inhibits cell growth at concentrations greater than 2.0 μM, no prolongation effect in mice and humans, may lead to drug resistance	Competitive inhibition of GAG-PrP interaction, unfolding of PrP-res, destablilization of PrP-res conformation, induces conformational change that disfavors PrPSc conformation	Scrapie, 263K, vCJD, sCJD, iatrogenic CJD, genetic CJD	140,188–193
E-64d	Cysteine protease inhibitor	Neuronal cell culture, mouse	No toxicity to cell growth at [ ] up to 100 μM, no prolongation effect	Competitive inhibition of GAG-PrP interaction, unfolding of PrP-res, destabilization of PrP-res conformation	Scrapie, 263K	140,190
MS-8209	Amphotericin B derivative	Neuronal cell culture, mouse, hamster	Prolongs incubation period (dose- and timing dependent), delays onset of PrP-res/GFAP accumulation, vacuolation, spongiosis, and astrogliosis in brain, variable efficacy across prion species	Potentially affects conversion, may interact with astrocyte lysosomal system and limit propagation of PrP at inoculation site	Sheep scrapie 127S, 139A, Sc237 (weaker with 139H), type 1 CJD, C506M3 (similar to ME7), 263K	129,194–200
31C6	Monoclonal anti-PrP antibody (residues 143–149), IgG1	Neuronal cell culture, mouse	Reduces PrPSc in cell culture (dose-dependent), no re-emergence following txt, mAb txt at 120 dpi increased survival (not statistically significant), slowed weight loss, disease progression, and accumulation ofPrPSc in brain	Direct inhibition of PrPC-PrPSc interaction by occupying binding domains, could interfere with PrPC metabolism by retaining PrPC on cell surface	Chandler (139A), RML	176,201
Doxycycline	Antibiotic	Neuronal cell culture, human	Variably affected PrP-res accumulation in culture, variable prolongation of survival, reduction in widespread & severe lesions (early txt)	Destabilize abnormal PrP, could operate at cell level by modulating formation of PrP aggregates	CJD (sporadic and genetic–E200K or V210I), sCJDMM1, sCJDVV2a, vCJDMM2b, iCJDMM1	202–206
Other
GSK2606414	Protein kinase RNA-like ER kinase (PERK) inhibitor	Mouse	Oral treatment reversed cognitive deficits and prevented clinical disease, effective pre-and post-symptomatic, halted progression in spongiform degeneration, protected from neuronal loss	Prevents activation of UPR branch that mediates prion neurotoxicity by inhibiting PERK	RML	207