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  • the Korean Society for Brain and Neural Sciences

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Original Article

Exp Neurobiol 2020; 29(1): 93-105

Published online February 29, 2020

https://doi.org/10.5607/en.2020.29.1.93

© The Korean Society for Brain and Neural Sciences

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

Jae Wook Hyeon1, Ran Noh1, Jiwon Choi2, Sol Moe Lee1, Yeong Seon Lee1, Seong Soo A. An3, Kyoung Tai No2,4 and Jeongmin Lee5*

1Division of Bacterial Disease Research, Center for Infectious Disease Research, Korea National Institute of Health, Centers for Disease Control and Prevention, Cheongju 28160, 2Bioinformatics and Molecular Design Research Center, Yonsei University, Seoul 03722, 3Gachon Bio Nano Research Institute, Gachon University, Seongnam 13120, 4Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, 5Division of Research Planning, Korea National Institute of Health, Centers for Disease Control and Prevention, Cheongju 28160, Korea

Correspondence to: *To whom correspondence should be addressed.
TEL: 82-43-719-8024, FAX: 82-43-719-8489
e-mail: jeongminlee@korea.kr

Received: November 6, 2019; Revised: February 4, 2020; Accepted: February 25, 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.

Prion diseases are a group of neurodegenerative and fatal central nervous system disorders. The pathogenic mechanism involves the conversion of cellular prion protein (PrPC) to an altered scrapie isoform (PrPSc), 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 PrPC to protease K (PK)-resistant PrPSc fragments (PrPres). 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 PrPSc-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 PrPres 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 PrPC was combined with BMD-42-2910. Our findings showed that BMD42-2910 sufficiently reduces PrPres generation in vitro and in vivo and may be a promising novel anti-prion compound.

Graphical Abstract


Keywords: Transmissible spongiform encephalopathy, Prion protein, Anti-prion, Derivatives, In silico