Developing Therapeutics for PrP Prion Diseases

Abstract

The prototypical PrP prion diseases are invariably fatal, and the search for agents to treat them spans more than 30 years, with limited success. However, in the last few years, the application of high-throughput screening, medicinal chemistry, and pharmacokinetic optimization has led to important advances. The PrP prion inoculation paradigm provides a robust assay for testing therapeutic efficacy, and a dozen compounds have been reported that lead to meaningful extension in survival of prion-infected mice. Here, we review the history and recent progress in the field, focusing on studies validated in animal models. Based on screens in cells infected with mouse-passaged PrP prions, orally available compounds were generated that double or even triple the survival of mice infected with the same prion strain. Unfortunately, no compounds have yet shown efficacy against human prions. Nevertheless, the speed of the recent advances brings hope that an effective therapeutic can be developed. A successful treatment for any neurodegenerative disease would be a major achievement, and the growing understanding that the more common neurodegenerative diseases, including Alzheimer's and Parkinson's, progress by an analogous prion mechanism serves to highlight the importance of antiprion therapeutics.

Figure 1.

Chemical structures of compounds used in early prion efficacy studies. (A) Congo red, (B) deuteroporphyrin IX 2,4-bis-(ethylene glycol) iron(III), (C) quinacrine, and (D) Compound B.

Figure 2.

PrP^Sc levels in the brains of RML-infected Mdr1^0/0 mice treated with quinacrine at 40 mg/kg per day for 60–90 days postinoculation (n = 3 for each point, shown as mean and standard error). (Figure reprinted from Ghaemmaghami et al. 2009, with permission from PLoS under the Creative Commons Attribution license.)

Figure 3.

Summary of preliminary structure–activity relationships (SARs) for 2-AMT analogs. The three rings are arbitrarily denoted A, B, and C for convenience. (Figure reprinted with Gallardo-Godoy et al. 2011, with permission from American Chemical Society © 2011.)

Figure 4.

Chemical structures and pharmacokinetic parameters of 2-AMT compounds, including brain C_max and AUC_last following a 10 mg/kg oral gavage.

Figure. 5.

Chemical structures and pharmacokinetic parameters of aryl amides, including brain C_max and AUC_last following a 10 mg/kg oral gavage.

Figure 6.

Survival curves of wild-type (A–C) and Tg(MoPrP) mice overexpressing PrP (D) inoculated with RML (A and D), ME7 (B), and 22L (C) prion strains. Mice were dosed with IND24 (green) or IND125 (blue) at 200 mg/kg/d, or vehicle (red), with dosing initiated 1 (solid lines) or 60 (dashed lines) days postinoculation (dpi), or 14 d before inoculation (dotted line). (A) Starting dosing with IND24 at 1 or 60 dpi in RML-inoculated mice produced a similar extension in survival; however, prophylactic dosing greatly increased survival. (B) ME7-inoculated mice showed a smaller survival extension when dosing was started at 60 dpi than at 1 dpi. (C) 22L-inoculated mice showed limited efficacy of IND24 when dosing was started at 60 dpi. (D) In mice overexpressing PrP, continuous dosing with IND24 approximately doubles and IND125 approximately triples the untreated incubation period of RML-inoculated mice.

Figure 7.

Chemical structures of additional compounds that extend survival of prion-infected mice. (A) Anle138b, (B) GN8, (C) LIN5044, and (D) BX912.