title: Structural insight into the antiprion compound inhibition mechanism of native prion folding over misfolding.
abstract: Transition of a physiological folded prion (PrPC) into a pathogenic misfolded prion (PrPSc) causes lethal neurodegenerative disorders and prion diseases. Antiprion compounds have been developed to prevent this conversion; however, their mechanism of action remains unclear. Recently, we reported two antiprion compounds, BMD29 and BMD35, identified by in silico and in vitro screening. In this study, we used extensive explicit-solvent molecular dynamics simulations to investigate ligand-binding inhibition by antiprion compounds in prion folding over misfolding behavior at acidic pH. The two antiprion compounds and the previously reported GN8 compound resulted in a remarkably stabilized intermediate by binding to the hotspot region of PrPC, whereas free PrPCand the inactive compound BMD01 destabilized the structure of PrPCleading to the misfolded form. The results uncovered a secondary structural transition of free PrPCand transition suppression by the antiprion compounds. One of the major misfolding processes in PrPC, alternation of hydrophobic core residues, disruption of intramolecular interactions, and the increase in residue solvent exposure were significantly inhibited by both antiprion compounds. These findings provide insights into prion misfolding and inhibition by antiprion compounds.
authors.affiliation: Bioinformatics and Molecular Design Research Center, Yonsei University, Seoul, Korea.
authors.forename: Jiwon
authors.initials: J
authors.lastname: Choi
authors.affiliation: Bioinformatics and Molecular Design Research Center, Yonsei University, Seoul, Korea.|Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Rajiv Gandhi
authors.identifier: 0000-0003-2364-5429
authors.initials: RG
authors.lastname: Govindaraj
authors.affiliation: Division of Zoonoses, Center for Immunology & Pathology, National Institute of Health, Korea Centers for Disease Control & Prevention, Seoul, Chungcheongbuk-do, Korea.
authors.forename: Jae Wook
authors.initials: JW
authors.lastname: Hyeon
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Kyungro
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: SongLing
authors.initials: S
authors.lastname: Ma
authors.affiliation: Division of Zoonoses, Center for Immunology & Pathology, National Institute of Health, Korea Centers for Disease Control & Prevention, Seoul, Chungcheongbuk-do, Korea.
authors.forename: Su Yeon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Division of Zoonoses, Center for Immunology & Pathology, National Institute of Health, Korea Centers for Disease Control & Prevention, Seoul, Chungcheongbuk-do, Korea.
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Lee
authors.affiliation: Bioinformatics and Molecular Design Research Center, Yonsei University, Seoul, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Kyoung Tai
authors.initials: KT
authors.lastname: No
mesh_terms: D001583:Benzoxazoles / Q000737:chemistry* / Q000494:pharmacology; D005663:Furans / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011328:Prions / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D017510:Protein Folding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D057165:Proteostasis Deficiencies; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C000624343:BMD29 compound; C000624344:BMD35 compound; D001583:Benzoxazoles; D005663:Furans; D011328:Prions; D013449:Sulfonamides
keywords: antiprion; essential dynamics; molecular dynamics simulations; prion misfolding; secondary structure