title: Development and characterization of monomeric N-end rule inhibitors through in vitro model substrates.
abstract: In the N-end rule pathway, a set of N-terminal amino acids, called N-degrons, are recognized and ubiquitinated by the UBR proteins. Here we examined various N-end rule inhibitors to identify essential structural components of the system. Our study using in vitro biochemical assay indicated that the l-conformation and protonated α-amino group of the first residue were critical for N-degrons to properly interact with the UBR proteins. The monomeric molecules with minimum interacting motifs showed endopeptidase resistance and better inhibitory activities than traditional dipeptide inhibitors. Collectively, our study identifies a pharmacophore of N-end rule inhibitors, which provides a structural platform to improve the efficiency and druggable properties of inhibitors. Considering that the N-end rule has been implicated in many pathophysiological processes in cells, inhibitors of this pathway, such as p-chloroamphetamine, are potentially of clinical interest in a novel aspect of action mechanisms.
authors: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors: Shashi
authors: S
authors: Sriram
authors: Jung Hoon
authors: JH
authors: Lee
authors: Binh Khanh
authors: BK
authors: Mai
authors: Yanxialei
authors: Y
authors: Jiang
authors: Yongho
authors: Y
authors: Kim
authors: Young Dong
authors: YD
authors: Yoo
authors: Rajkumar
authors: R
authors: Banerjee
authors: Seung-Han
authors: SH
authors: Lee
authors: Min Jae
authors: MJ
authors: Lee
mesh_terms: D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D008958:Models, Molecular; D011487:Protein Conformation; D013237:Stereoisomerism; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D044767:Ubiquitin-Protein Ligases