Insights from Therapeutic Studies for PrP Prion Disease

Teruya, Kenta; Doh‐ura, Katsumi

doi:10.1101/cshperspect.a024430

Cited by 33 publications

(26 citation statements)

References 136 publications

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“…Few of these molecules, such as quinacrine [ 6 – 9 ], pentosan polysulfate [ 10 – 13 ] and doxycycline [ 14 , 15 ], even reached the clinical phase. However, so far none of these approaches have shown efficacy in patients [ 16 ]. Moreover, several previous studies have raised concerns regarding the general concept of targeting PrP Sc .…”

Section: Introductionmentioning

confidence: 99%

An antipsychotic drug exerts anti-prion effects by altering the localization of the cellular prion protein

et al. 2017

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Prion diseases are neurodegenerative conditions characterized by the conformational conversion of the cellular prion protein (PrPC), an endogenous membrane glycoprotein of uncertain function, into PrPSc, a pathological isoform that replicates by imposing its abnormal folding onto PrPC molecules. A great deal of evidence supports the notion that PrPC plays at least two roles in prion diseases, by acting as a substrate for PrPSc replication, and as a mediator of its toxicity. This conclusion was recently supported by data suggesting that PrPC may transduce neurotoxic signals elicited by other disease-associated protein aggregates. Thus, PrPC may represent a convenient pharmacological target for prion diseases, and possibly other neurodegenerative conditions. Here, we sought to characterize the activity of chlorpromazine (CPZ), an antipsychotic previously shown to inhibit prion replication by directly binding to PrPC. By employing biochemical and biophysical techniques, we provide direct experimental evidence indicating that CPZ does not bind PrPC at biologically relevant concentrations. Instead, the compound exerts anti-prion effects by inducing the relocalization of PrPC from the plasma membrane. Consistent with these findings, CPZ also inhibits the cytotoxic effects delivered by a PrP mutant. Interestingly, we found that the different pharmacological effects of CPZ could be mimicked by two inhibitors of the GTPase activity of dynamins, a class of proteins involved in the scission of newly formed membrane vesicles, and recently reported as potential pharmacological targets of CPZ. Collectively, our results redefine the mechanism by which CPZ exerts anti-prion effects, and support a primary role for dynamins in the membrane recycling of PrPC, as well as in the propagation of infectious prions.

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Section: Introductionmentioning

confidence: 99%

An antipsychotic drug exerts anti-prion effects by altering the localization of the cellular prion protein

et al. 2017

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“…Existing anti-prion compounds include those described in library databases, FDA approved drugs for treating other diseases, natural products, antibodies, peptides and derivatives [12]. The inhibitory effects of these compounds on PrP res are reliably identified in PrP Sc -infected cell models; however, therapeutic effects are not often observed in PrP Sc -infected mice, and clinical trials have been unsuccessful to date [13]. An advantage of exploring antiprion compounds in silico is that it enables simulated binding of the compounds to PrP C in virtual cellular environments.…”

Section: Discussionmentioning

confidence: 99%

“…Current knowledge on prion diseases has revealed potential therapeutic strategies, including the prevention of the conversion to PrP aggregates, induction of degradation of these aggregates, destabilization the PrP Sc structure, or interference with PrP C /PrP Sc cellular uptake [11]. Therapeutic trials have been conducted using a wide variety of potential prion diseases treatments, and numerous compounds have been extensively investigated to demonstrate anti-prion activity in cell culture models [12][13][14]. However, no current treatment has sufficient activity to halt disease progression in infected animal models.…”

Section: Introductionmentioning

confidence: 99%

BMD42-2910, a Novel Benzoxazole Derivative, Shows a Potent Anti-prion Activity and Prolongs the Mean Survival in an Animal Model of Prion Disease

et al. 2020

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Prion diseases are a group of neurodegenerative and fatal central nervous system disorders. The pathogenic mechanism involves the conversion of cellular prion protein (PrP C) to an altered scrapie isoform (PrP Sc), which accumulates in amyloid deposits in the brain. However, no therapeutic drugs have demonstrated efficacy in clinical trials. We previously reported that BMD42-29, a synthetic compound discovered in silico, is a novel anti-prion compound that inhibits the conversion of PrP C to protease K (PK)-resistant PrP Sc fragments (PrP res). In the present study, 14 derivatives of BMD42-29 were obtained from BMD42-29 by modifying in the side chain by in silico feedback, with the aim to determine whether they improve anti-prion activity. These derivatives were assessed in a PrP Sc-infected cell model and some derivatives were further tested using real timequaking induced conversion (RT-QuIC). Among them, BMD42-2910 showed high anti-prion activity at low concentrations in vitro and also no toxic effects in a mouse model. Interestingly, abundant PrP res was reduced in brains of mice infected with prion strain when treated with BMD42-2910, and the mice survived longer than control mice and even that treated with BMD42-29. Finally, high binding affinity was predicted in the virtual binding sites (Asn159, Gln 160, Lys194, and Glu196) when PrP C was combined with BMD-42-2910. Our findings showed that BMD42-2910 sufficiently reduces PrP res generation in vitro and in vivo and may be a promising novel anti-prion compound.

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“…While some therapeutic potential would be highly desirable in the human field, the number of cases likely to occur is too low to drive this as a commercial interest. Some chemicals such as pentosan or doxycycline are thought to delay disease progression in humans (Teruya & Doh‐Ura, ; Varges et al., ), and antibody therapies have been investigated experimentally (Burchell & Panegyres, ). The literature in this area is sparse and in places appears contradictory.…”

Section: Main Means Of Prevention Detection and Controlmentioning

confidence: 99%

DISCONTOOLS: Identifying gaps in controlling bovine spongiform encephalopathy

Simmons¹,

Ru²,

Casalone³

et al. 2017

Transbound Emerg Dis

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SummaryThis article summarizes the 2016 update of the DISCONTOOLS project gap analysis on bovine spongiform encephalopathy (BSE), which was based on a combination of literature review and expert knowledge. Uncertainty still exists in relation to the pathogenesis, immunology and epidemiology of BSE, but provided that infected material is prohibited from entering the animal feed chain, cases should continue to decline. BSE does not appear to spread between cattle, but if new strains with this ability appear then control would be considerably more difficult. Atypical types of BSE (L-BSE and H-BSE) have been identified, which have different molecular patterns and pathology, and do not display the same clinical signs as classical BSE. Laboratory transmission experiments indicate that the L-BSE agent has zoonotic potential. There is no satisfactory conclusion regarding the origin of the BSE epidemic. C-BSE case numbers declined rapidly following strict controls banning ruminant protein in animal feed, but occasional cases still occur. It is unclear whether these more recent cases indicate inadequate implementation of the bans, or the possibility that C-BSE might occur spontaneously, as has been postulated for H-and L-BSE. All of this will have implications once existing bans and levels of surveillance are both relaxed. Immunochemical

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Insights from Therapeutic Studies for PrP Prion Disease

Cited by 33 publications

References 136 publications

An antipsychotic drug exerts anti-prion effects by altering the localization of the cellular prion protein

An antipsychotic drug exerts anti-prion effects by altering the localization of the cellular prion protein

BMD42-2910, a Novel Benzoxazole Derivative, Shows a Potent Anti-prion Activity and Prolongs the Mean Survival in an Animal Model of Prion Disease

DISCONTOOLS: Identifying gaps in controlling bovine spongiform encephalopathy

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