title: Immunoproteasome β5i-Selective Dipeptidomimetic Inhibitors.
abstract: N,C-capped dipeptides belong to a class of noncovalent proteasome inhibitors. Herein we report that the insertion of a β-amino acid into N,C-capped dipeptides markedly decreases their inhibitory potency against human constitutive proteasome β5c, while maintaining potent inhibitory activity against human immunoproteasome β5i, thereby achieving thousands-fold selectivity for β5i over β5c. Structure-activity relationship studies revealed that β5c does not tolerate the β-amino acid based dipeptidomimetics as does β5i. In vitro, one such compound was found to inhibit human T cell proliferation. Compounds of this class may have potential as therapeutics for autoimmune and inflammatory diseases with less mechanism-based cytotoxicity than agents that also inhibit the constitutive proteasome.
authors: Department of Biochemistry, The Abby and Howard Milstein Synthetic Chemistry Core Facility, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA.
authors: Pradeep K
authors: PK
authors: Singh
authors: Department of Microbiology & Immunology, Weill Cornell Medical College, 1300 York Avenue, Box 62, New York, NY, 10065, USA.
authors: Hao
authors: H
authors: Fan
authors: Department of Microbiology & Immunology, Weill Cornell Medical College, 1300 York Avenue, Box 62, New York, NY, 10065, USA.
authors: Xiuju
authors: X
authors: Jiang
authors: Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA.
authors: Lei
authors: L
authors: Shi
authors: Department of Microbiology & Immunology, Weill Cornell Medical College, 1300 York Avenue, Box 62, New York, NY, 10065, USA.
authors: Carl F
authors: CF
authors: Nathan
authors: Department of Microbiology & Immunology, Weill Cornell Medical College, 1300 York Avenue, Box 62, New York, NY, 10065, USA. gal2005@med.cornell.edu.
authors: Gang
authors: G
authors: Lin
mesh_terms: D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D004151:Dipeptides; D057786:Peptidomimetics; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex
keywords: T cells; autoimmune; immunosuppression; peptidomimetics; β-amino acids; β5i-selective inhibitors