Cargando…

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

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 h...

Descripción completa

Detalles Bibliográficos
Autores principales: Hyeon, Jae Wook, Noh, Ran, Choi, Jiwon, Lee, Sol Moe, Lee, Yeong Seon, An, Seong Soo A., No, Kyoung Tai, Lee, Jeongmin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Korean Society for Brain and Neural Sciences 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075655/
https://www.ncbi.nlm.nih.gov/pubmed/32122111
http://dx.doi.org/10.5607/en.2020.29.1.93
_version_ 1783507067601944576
author Hyeon, Jae Wook
Noh, Ran
Choi, Jiwon
Lee, Sol Moe
Lee, Yeong Seon
An, Seong Soo A.
No, Kyoung Tai
Lee, Jeongmin
author_facet Hyeon, Jae Wook
Noh, Ran
Choi, Jiwon
Lee, Sol Moe
Lee, Yeong Seon
An, Seong Soo A.
No, Kyoung Tai
Lee, Jeongmin
author_sort Hyeon, Jae Wook
collection PubMed
description 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 time-quaking 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.
format Online
Article
Text
id pubmed-7075655
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher The Korean Society for Brain and Neural Sciences
record_format MEDLINE/PubMed
spelling pubmed-70756552020-03-23 BMD42-2910, a Novel Benzoxazole Derivative, Shows a Potent Anti-prion Activity and Prolongs the Mean Survival in an Animal Model of Prion Disease Hyeon, Jae Wook Noh, Ran Choi, Jiwon Lee, Sol Moe Lee, Yeong Seon An, Seong Soo A. No, Kyoung Tai Lee, Jeongmin Exp Neurobiol Original Article 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 time-quaking 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 Korean Society for Brain and Neural Sciences 2020-02 2020-02-29 /pmc/articles/PMC7075655/ /pubmed/32122111 http://dx.doi.org/10.5607/en.2020.29.1.93 Text en Copyright © Experimental Neurobiology 2020 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Hyeon, Jae Wook
Noh, Ran
Choi, Jiwon
Lee, Sol Moe
Lee, Yeong Seon
An, Seong Soo A.
No, Kyoung Tai
Lee, Jeongmin
BMD42-2910, a Novel Benzoxazole Derivative, Shows a Potent Anti-prion Activity and Prolongs the Mean Survival in an Animal Model of Prion Disease
title BMD42-2910, a Novel Benzoxazole Derivative, Shows a Potent Anti-prion Activity and Prolongs the Mean Survival in an Animal Model of Prion Disease
title_full BMD42-2910, a Novel Benzoxazole Derivative, Shows a Potent Anti-prion Activity and Prolongs the Mean Survival in an Animal Model of Prion Disease
title_fullStr BMD42-2910, a Novel Benzoxazole Derivative, Shows a Potent Anti-prion Activity and Prolongs the Mean Survival in an Animal Model of Prion Disease
title_full_unstemmed BMD42-2910, a Novel Benzoxazole Derivative, Shows a Potent Anti-prion Activity and Prolongs the Mean Survival in an Animal Model of Prion Disease
title_short BMD42-2910, a Novel Benzoxazole Derivative, Shows a Potent Anti-prion Activity and Prolongs the Mean Survival in an Animal Model of Prion Disease
title_sort bmd42-2910, a novel benzoxazole derivative, shows a potent anti-prion activity and prolongs the mean survival in an animal model of prion disease
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075655/
https://www.ncbi.nlm.nih.gov/pubmed/32122111
http://dx.doi.org/10.5607/en.2020.29.1.93
work_keys_str_mv AT hyeonjaewook bmd422910anovelbenzoxazolederivativeshowsapotentantiprionactivityandprolongsthemeansurvivalinananimalmodelofpriondisease
AT nohran bmd422910anovelbenzoxazolederivativeshowsapotentantiprionactivityandprolongsthemeansurvivalinananimalmodelofpriondisease
AT choijiwon bmd422910anovelbenzoxazolederivativeshowsapotentantiprionactivityandprolongsthemeansurvivalinananimalmodelofpriondisease
AT leesolmoe bmd422910anovelbenzoxazolederivativeshowsapotentantiprionactivityandprolongsthemeansurvivalinananimalmodelofpriondisease
AT leeyeongseon bmd422910anovelbenzoxazolederivativeshowsapotentantiprionactivityandprolongsthemeansurvivalinananimalmodelofpriondisease
AT anseongsooa bmd422910anovelbenzoxazolederivativeshowsapotentantiprionactivityandprolongsthemeansurvivalinananimalmodelofpriondisease
AT nokyoungtai bmd422910anovelbenzoxazolederivativeshowsapotentantiprionactivityandprolongsthemeansurvivalinananimalmodelofpriondisease
AT leejeongmin bmd422910anovelbenzoxazolederivativeshowsapotentantiprionactivityandprolongsthemeansurvivalinananimalmodelofpriondisease