title: Generation of a unique small molecule peptidomimetic that neutralizes lupus autoantibody activity.
abstract: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of pathogenic autoantibodies, many of which are directed against nuclear antigens, in particular double-stranded (ds) DNA. Both clinical studies and animal models have shown that anti-dsDNA antibodies contribute to kidney disease, which is present in 50% of lupus patients and is a major cause of mortality. We previously demonstrated that a subset of nephrotoxic anti-dsDNA antibodies also recognizes the pentapeptide consensus sequence D/E W D/E Y S/G (DWEYS) present in the NR2A and NR2B subunits of the N-methyl-d-aspartate receptor (NMDAR). Autoantibodies with this specificity are present in ≈40% of lupus patient sera and are both nephrotoxic and neurotoxic. Elevated titers are present in cerebrospinal fluid of patients with central nervous system manifestations of SLE. Administration of the nonnaturally occurring D form of the DWEYS pentapeptide prevents these antibodies from depositing in glomeruli and from mediating neuronal excitotoxicity. To craft a more useful therapeutic, we used the structural features of the DWEYS peptide to design a unique, selective, and potent small molecule peptidomimetic, FISLE-412, which neutralizes anti-dsDNA/NMDAR lupus autoantibodies and prevents their pathogenic interaction with tissue antigens. This compound, or others derived from it, may provide a unique strategy for the development of lupus therapeutics.
authors.affiliation: Laboratory of Neuroimmunology, Autoimmune and Musculoskeletal Disease Center, Department of Medicinal Chemistry, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors.forename: Ona
authors.initials: O
authors.lastname: Bloom
authors.forename: Kai Fan
authors.initials: KF
authors.lastname: Cheng
authors.forename: Kai Fen
authors.initials: KF
authors.lastname: Cheng
authors.forename: Mingzhu
authors.initials: M
authors.lastname: He
authors.forename: Angelos
authors.initials: A
authors.lastname: Papatheodorou
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Volpe
authors.forename: Betty
authors.initials: B
authors.lastname: Diamond
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D010455:Peptides / Q000235:genetics / Q000276:immunology; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology* / Q000627:therapeutic use*
chemical_list: D001323:Autoantibodies; D010455:Peptides; D057786:Peptidomimetics