title: pH-Dependent In-Cell Self-Assembly of Peptide Inhibitors Increases the Anti-Prion Activity While Decreasing the Cytotoxicity.
abstract: The first step in the conventional approach to self-assembled biomaterials is to develop well-defined nanostructures in vitro, which is followed by disruption of the preformed nanostructures at the inside of the cell to achieve bioactivity. Here, we propose an inverse strategy to develop in-cell gain-of-function self-assembled nanostructures. In this approach, the supramolecular building blocks exist in a unimolecular/unordered state in vitro or at the outside of the cell and assemble into well-defined nanostructures after cell internalization. We used block copolypeptides of an oligoarginine and a self-assembling peptide as building blocks and investigated correlations among the nanostructural state, antiprion bioactivity, and cytotoxicity. The optimal bioactivity (i.e., the highest antiprion activity and lowest cytotoxicity) was obtained when the building blocks existed in a unimolecular/unordered state in vitro and during the cell internalization process, exerting minimal cytotoxic damage to cell membranes, and were subsequently converted into high-charge-density vesicles in the low pH endosome/lysosomes in vivo, thus, resulting in the significantly enhanced antiprion activity. In particular, the in-cell self-assembly concept presents a feasible approach to developing therapeutics against protein misfolding diseases. In general, the in-cell self-assembly provides a novel inverse methodology to supramolecular bionanomaterials.
authors.affiliation: Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University , Gyeonggi-do 15588, Republic of Korea.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Waqas
authors.affiliation: Department of Materials Science and Engineering, Yonsei University , Seoul 03722, Republic of Korea.
authors.forename: Woo-Jin
authors.initials: WJ
authors.lastname: Jeong
authors.affiliation: Department of Materials Science and Engineering, Yonsei University , Seoul 03722, Republic of Korea.
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University , Gyeonggi-do 15588, Republic of Korea.
authors.forename: Dae-Hwan
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University , Gyeonggi-do 15588, Republic of Korea.
authors.forename: Chongsuk
authors.initials: C
authors.lastname: Ryou
authors.affiliation: Department of Materials Science and Engineering, Yonsei University , Seoul 03722, Republic of Korea.
authors.forename: Yong-Beom
authors.identifier: 0000-0001-6590-7373
authors.initials: YB
authors.lastname: Lim
mesh_terms: D001672:Biocompatible Materials / Q000737:chemistry; D002453:Cell Cycle; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D046529:Microscopy, Electron, Transmission; D049329:Nanostructures / Q000737:chemistry*; D010455:Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011328:Prions / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D001672:Biocompatible Materials; D010455:Peptides; D011328:Prions