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

Abstract

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.

The engineered peptide construct NCAM1-Aβ inhibits aggregation of the human prion protein (PrP)

“…The toxic species in amyloid and prion diseases are generally considered to be small toxic oligomeric aggregates (Sengupta and Udgaonkar, 2018;Verma et al, 2015), but so far no drugs or treatments that target such aggregates have been approved against prion diseases (Hyeon et al, 2020;Lee et al, 2019;Mashima et al, 2020). Potential drug molecules may interfere with oligomer formation in various ways: by reducing production of the protein, by inhibiting its aggregation, by diverting the aggregation pathway(s) towards non-toxic forms, or by reducing the lifetime of the toxic forms, for example by promoting rapid aggregation into larger non-toxic aggregates.…”

Prion therapeutics: Lessons from the past

“… Compound Class Structure Administration route Target MOA Toxicity/BBB penetration Status Ref Anle138b Diphenylpyrazole derivatives Oral PrP C Inhibit PrP Sc oligomerization Safe up to 300 mg/day Phase 1b study PD patients ongoing [ 79–83 ] BMD42-2910 Benzoxazole derivative i.c. PrP C Chaperone Reduce PrP Sc accumulation Non-toxic up to 100 mg/Kg /day in mice in vivo [ 45 , 46 ] Congo red Diazo dye Subcutaneous, i.p. PrP C /PrP Sc Block PrP Sc generation Toxic Poor BBB permeation Non-specific binding to PrP C In vitro, In vivo (early) [ 59–72 ] Cyclodextran Sulphated polyanions PrP C Chaperone Inhibit PrP Sc Oligomerization Non-toxic effects (5 mg/kg BW per day) In vitro [ 129 , 130 ] Dextran sulphate Su...…”

“…BMD42-2910 is a recently discovered anti-prion agent, which exhibited low EC 50 in vitro without toxic effects in the mouse model [ 45 , 46 ]. The compound significantly reduced PrP Sc in prion-infected mice brains and extended the survival time.…”

The engineered peptide construct NCAM1-Aβ inhibits fibrillization of the human prion protein (PrP)

“…The toxic species in amyloid and prion diseases are generally considered to be small toxic oligomeric aggregates (Verma et al, 2015;Sengupta & Udgaonkar, 2018;Sang et al, 2019), but so far no drugs or treatments that target such aggregates have been approved against prion diseases (Lee et al, 2019;Hyeon et al, 2020;Mashima et al, 2020). Potential drug molecules may interfere with oligomer formation in various ways: by reducing production of the protein, by inhibiting its aggregation, by diverting the aggregation pathway(s) towards non-toxic forms, or by reducing the lifetime of the toxic forms, for example by promoting rapid aggregation into larger non-toxic aggregates.…”