title: Alkylating antitumor drug mechlorethamine conceals a structured PrP domain and inhibits in vitro prion amplification.
abstract: Prion diseases are a group of incurable transmissible neurodegenerative disorders. The key molecular event in the pathogenesis of prion diseases is the conversion of the cellular prion protein (PrP(C)) into its pathological isoform (PrP(Sc)), accompanied by a conformational transition of α-helix into β-sheet structure involving the structured α-helix 1 domain from residues 144-154 of the protein (PrP144-154). Blocking the accessibility of PrP144-152 with anti-PrP antibody 6H4 was found to prevent PrP conversion and even to cure prion infection in cell models ( Enari et al. 2001 ). Previously,  Yuan et al. (2005 ) demonstrated that the reduction and alkylation of PrP induced concealment of the 6H4 epitope. This study examined the ability of mechlorethamine (MCT), an alkylating antitumor drug, to conceal the 6H4 epitope and block PrP conversion in the presence of a reducing reagent. Mechlorethamine treatment significantly decreased in vitro amplification of PrP(Sc) in the highly efficient protein misfolding cyclic amplification system. Our findings suggest that MCT may serve as a potential therapeutic agent for prion diseases.
authors: Department of Pathology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors: Xiaochen
authors: X
authors: Zhou
authors: Hao
authors: H
authors: Bi
authors: Justin
authors: J
authors: Wong
authors: Miyuki
authors: M
authors: Shimoji
authors: Yifan
authors: Y
authors: Wang
authors: Jue
authors: J
authors: Yuan
authors: Xiangzhu
authors: X
authors: Xiao
authors: Gong-Xian
authors: GX
authors: Wang
authors: Wen-Quan
authors: WQ
authors: Zou
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology* / Q000627:therapeutic use; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008466:Mechlorethamine / Q000494:pharmacology* / Q000627:therapeutic use; D018621:PrPC Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D017096:Prion Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017510:Protein Folding / Q000187:drug effects; D020033:Protein Isoforms; D017433:Protein Structure, Secondary / Q000187:drug effects
chemical_list: D018906:Antineoplastic Agents, Alkylating; D000939:Epitopes; D018621:PrPC Proteins; D020033:Protein Isoforms; D008466:Mechlorethamine