title: Small molecules enhance functional O-mannosylation of Alpha-dystroglycan.
abstract: Alpha-dystroglycan (α-DG), a highly glycosylated receptor for extracellular matrix proteins, plays a critical role in many biological processes. Hypoglycosylation of α-DG results in various types of muscular dystrophies and is also highly associated with progression of majority of cancers. Currently, there are no effective treatments for those devastating diseases. Enhancing functional O-mannosyl glycans (FOG) of α-DG on the cell surfaces is a potential approach to address this unmet challenge. Based on the hypothesis that the cells can up-regulate FOG of α-DG in response to certain chemical stimuli, we developed a cell-based high-throughput screening (HTS) platform for searching chemical enhancers of FOG of α-DG from a large chemical library with 364,168 compounds. Sequential validation of the hits from a primary screening campaign and chemical works led to identification of a cluster of compounds that positively modulate FOG of α-DG on various cell surfaces including patient-derived myoblasts. These compounds enhance FOG of α-DG by almost ten folds, which provide us powerful tools for O-mannosylation studies and potential starting points for the development of drug to treat dystroglycanopathy.
authors.affiliation: Chemical & Molecular Engineering College, East China Normal University, North Zhongshan Road 3663, Shanghai 200062, China.
authors.forename: Fengping
authors.initials: F
authors.lastname: Lv
authors.affiliation: Mannan Pharmaceuticals LLC, 900B W. Faris Road Suite 700, Greenville, SC 29605, USA; Roc Institute for Arts and Sciences, 1632 Penderlea Lane, NC 28105, USA.
authors.forename: Zhi-Fang
authors.initials: ZF
authors.lastname: Li
authors.affiliation: Chemical & Molecular Engineering College, East China Normal University, North Zhongshan Road 3663, Shanghai 200062, China. Electronic address: whu@chem.ecnu.edu.cn.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Hu
authors.affiliation: Mannan Pharmaceuticals LLC, 900B W. Faris Road Suite 700, Greenville, SC 29605, USA; Roc Institute for Arts and Sciences, 1632 Penderlea Lane, NC 28105, USA. Electronic address: xwu@mannanpharma.com.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Wu
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical / Q000379:methods; D049030:Dystroglycans / Q000378:metabolism*; D006031:Glycosylation / Q000187:drug effects*; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D008358:Mannose / Q000378:metabolism*; D051379:Mice; D009136:Muscular Dystrophies / Q000188:drug therapy / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D054852:Small Molecule Libraries; D049030:Dystroglycans; D008358:Mannose
keywords: Cell-based high-throughput screening; Dystroglycan; Dystroglycanopathy; O-Mannosylation