Different 2-Aminothiazole Therapeutics Produce Distinct Patterns of Scrapie Prion Neuropathology in Mouse Brains

Giles, Kurt; Berry, David B.; Condello, Carlo; Hawley, Ralph C.; Gallardo-Godoy, Alejandra; Bryant, Clifford; Oehler, Abby; Elepano, Manuel; Bhardwaj, Sumita; Patel, Smita S.; Silber, B. Michael; Guan, Shenheng; DeArmond, Stephen J.; Renslo, Adam R.; Prusiner, Stanley B.

doi:10.1124/jpet.115.224659

Cited by 46 publications

(63 citation statements)

References 40 publications

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“…Studies with IND24 showed unexpected effects on efficacy when dosing was started later and when the mouse models and prion strains were varied (Berry et al, 2013;Berry et al, 2015;Giles et al, 2015). In addition, prophylactic dosing with IND24 was more effective at extending survival than continuous dosing starting after inoculation .…”

Section: Discussionmentioning

confidence: 99%

“…Such compounds were extended to long-term efficacy studies. We have now reported efficacy for 10 compounds in RML-infected mice: six 2-AMTs (Berry et al, 2013;Giles et al, 2015) and the four aryl amides described here. Remarkably, all 10 extend the survival of prion-infected mice, many by 2-fold or more.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to mouse-passaged prion strains, IND24 was effective against CWD prions from deer and elk but was ineffective against two isolates of sheep scrapie (Berry et al, 2013;Berry et al, 2015); however, IND24 and all other compounds tested to date failed to extend the survival of Tg mice expressing either human PrP or a chimeric human/ mouse PrP that were each infected with human CJD prions (Berry et al, 2013;Lu et al, 2013;Giles et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Aryl Amides Are Not Efficacious against CJD Prions. None of the compounds reported to date that extend survival of mice infected with mouse-passaged prion strains shows efficacy against mice inoculated with CJD prions (Berry et al, 2013;Lu et al, 2013;Giles et al, 2015). We therefore inoculated Tg1014 mice expressing a chimeric human/mouse PrP (Giles et al, 2010) with sCJD(MM1) prions and treated them with each of the aryl amides at the same dose shown to be effective against RML prions.…”

Section: Aryl Amides As Anti-prion Therapeuticsmentioning

confidence: 99%

“…Using prion-infected cells for screening assays, multiple compounds have been identified that double the survival of mice inoculated with mouse-passaged prions, including Compound B (Kawasaki et al, 2007), Anle138b (Wagner et al, 2013), and a series with the 2-aminothiazole (2-AMT) chemical scaffold (Berry et al, 2013;Giles et al, 2015). When prions from the brains of mice treated with 2-AMT IND24 (Berry et al, 2013) were used to infect CAD5 cells, the resulting strain was resistant to IND24, raising the specter that small molecule intervention could lead to drug resistance, a concept that had been suggested by other studies (Ghaemmaghami et al, 2009;Oelschlegel and Weissmann, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Optimization of Aryl Amides that Extend Survival in Prion-Infected Mice

Giles

Berry

Condello

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Developing therapeutics for neurodegenerative diseases (NDs) prevalent in the aging population remains a daunting challenge. With the growing understanding that many NDs progress by conformational self-templating of specific proteins, the prototypical prion diseases offer a platform for ND drug discovery. We evaluated high-throughput screening hits with the aryl amide scaffold and explored the structure-activity relationships around three series differing in their N-aryl core: benzoxazole, benzothiazole, and cyano. Potent anti-prion compounds were advanced to pharmacokinetic studies, and the resulting brainpenetrant leads from each series, together with a related N-aryl piperazine lead, were escalated to long-term dosing and efficacy studies. Compounds from each of the four series doubled the survival of mice infected with a mouse-passaged prion strain. Treatment with aryl amides altered prion strain properties, as evidenced by the distinct patterns of neuropathological deposition of prion protein and associated astrocytic gliosis in the brain; however, none of the aryl amide compounds resulted in drug-resistant prion strains, in contrast to previous studies on compounds with the 2-aminothiazole (2-AMT) scaffold. As seen with 2-AMTs and other effective anti-prion compounds reported to date, the novel aryl amides reported here were ineffective in prolonging the survival of transgenic mice infected with human prions. Most encouraging is our discovery that aryl amides show that the development of drug resistance is not an inevitable consequence of efficacious anti-prion therapeutics.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Aryl Amides As Anti-prion Therapeuticsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Optimization of Aryl Amides that Extend Survival in Prion-Infected Mice

Giles

Berry

Condello

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Juvenile Gerstmann‐Sträussler‐Scheinker Disease Mimicking Anticipation Phenomenon

Yoshinaga Tonholo Silva,

Oliveira Marques,

Zanoteli

et al. 2023

Movement Disord Clin Pract

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Towards authentic transgenic mouse models of heritable PrP prion diseases

et al. 2016

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Attempts to model inherited human prion disorders such as familial Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS) disease, and fatal familial insomnia (FFI) using genetically modified mice have produced disappointing results. We recently demonstrated that transgenic (Tg) mice expressing wild-type bank vole prion protein (BVPrP) containing isoleucine at polymorphic codon 109 develop a spontaneous neurodegenerative disorder that exhibits many of the hallmarks of prion disease. To determine if mutations causing inherited human prion disease alter this phenotype, we generated Tg mice expressing BVPrP containing the D178N mutation, which causes FFI; the E200K mutation, which causes familial CJD; or an anchorless PrP mutation similar to mutations that cause GSS. Modest expression levels of mutant BVPrP resulted in highly penetrant spontaneous disease in Tg mice, with mean ages of disease onset ranging from ~120 to ~560 days. The brains of spontaneously ill mice exhibited prominent features of prion disease specific neuropathology that were unique to each mutation and distinct from Tg mice expressing wild-type BVPrP. An ~8 kDa proteinase K resistant PrP fragment was found in the brains of spontaneously ill Tg mice expressing either wild-type or mutant BVPrP. The spontaneously formed mutant BVPrP prions were transmissible to Tg mice expressing wild-type or mutant BVPrP as well as to Tg mice expressing mouse PrP. Thus, Tg mice expressing mutant BVPrP exhibit many of the hallmarks of heritable prion disorders in humans including spontaneous disease, protease-resistant PrP, and prion infectivity.

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Different 2-Aminothiazole Therapeutics Produce Distinct Patterns of Scrapie Prion Neuropathology in Mouse Brains

Cited by 46 publications

References 40 publications

Optimization of Aryl Amides that Extend Survival in Prion-Infected Mice

Optimization of Aryl Amides that Extend Survival in Prion-Infected Mice

Juvenile Gerstmann‐Sträussler‐Scheinker Disease Mimicking Anticipation Phenomenon

Towards authentic transgenic mouse models of heritable PrP prion diseases

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