Advancing targeted protein degradation for metabolic diseases therapy. (February 2023)

• Record Type: Journal Article
• Authors: Zhou, Qian-Qian; Xiao, Hai-Tao; Yang, Fan; Wang, Yong-Dan; Li, Ping; Zheng, Zu-Guo
• Is Part Of: Pharmacological research. Volume 188(2023)
• Publication Date: 2023-02
• Subjects: AUTAC autophagy-targeting chimera -- ATTEC autophagosome-tethering compound -- AUTOTAC autophagy-targeting chimera- -- ApoC-III apolipoprotein CIII -- ANGPTL3 angioimonegen-like protein 3 -- ASOs antisense oligonucleotides -- ApoE apolipoprotein E -- ALP autophagy-lysosomal pathway -- AR androgen receptor -- CMA chaperone-mediated autophagy -- CRISPR-Cas9 clustered regularly interspaced short palindromic repeats-associated protein 9 -- CRBN cereblon -- CA carnosic acid -- E1 ubiquitin-activating enzymes -- E2 ubiquitin-conjugating enzymes -- E3 ubiquitin-protein ligases -- ER estrogen receptor -- ERRα Estrogen-related receptor alpha -- FABP4 fatty acid binding protein 4 -- FA fatty acids -- FLD fatty liver disease -- HFD high-fat diet -- HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A -- HMGCR HMG-CoA reductase -- Halo dehalogenase -- LYTACs lysosome targeting chimeras -- LTR lysosomal targeting receptor -- LAMP2A Lysosome-Associated Membrane Protein 2A -- LD lipid droplets -- LXRα and LXRβ liver X receptors α and β -- MetS metabolic syndrome -- MG molecular glues -- mAbs monoclonal antibodies -- M6Pn mannose-6-phosphonate -- miRNA microRNA -- PROTACs proteolysis targeting chimeras -- POI protein-of-interest -- PPI protein-protein interaction -- PK pharmacokinetic -- PD pharmacodynamics -- PBD protein binding domain -- PNPLA3 patatin-like phospholipase domain-containing 3 -- PI3K phosphatidylinositol 3-kinase -- PDEδ prenyl-protein chaperone -- siRNA small interfering RNA -- SREBP sterol regulatory element binding protein -- SCAP SREBP cleavage activating protein -- SQSTM1 sequentosome 1 -- TPD targeted protein degradation -- TG triglyceride -- TBM targeted-binding moiety -- TC total cholesterol -- UPS ubiquitin-proteasome system -- VHL von Hippel-Lindau; Target protein degradation -- PROTACs -- MG -- ATTEC -- Metabolic syndrome; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106627
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: The development and application of traditional drugs represented by small molecule chemical drugs and biological agents, especially inhibitors, have become the mainstream drug development. In recent years, targeted protein degradation (TPD) technology has become one of the most promising methods to remove specific disease-related proteins using cell self-destruction mechanisms. Many different TPD strategies are emerging based on the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP), including but not limited to proteolysis-targeting chimeras (PROTAC), molecular glues (MG), lysosome targeting chimeras (LYTAC), chaperone-mediated autophagy (CMA)-targeting chimeras, autophagy-targeting chimera (AUTAC), autophagosome-tethering compound (ATTEC), and autophagy-targeting chimera (AUTOTAC). The advent of targeted degradation technology can change most protein targets in human cells from undruggable to druggable, greatly expanding the therapeutic prospect of refractory diseases such as metabolic syndrome. Here, we summarize the latest progress of major TPD technologies, especially in metabolic syndrome and look forward to providing new insights for drug discovery. Graphical Abstract: ga1