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Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10255-9. doi: 10.1073/pnas.1103555108. Epub 2011 Jun 6.

Generation of a unique small molecule peptidomimetic that neutralizes lupus autoantibody activity.

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  • 1Laboratory of Neuroimmunology, Autoimmune and Musculoskeletal Disease Center, Department of Medicinal Chemistry, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.

Erratum in

  • Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18566. Cheng, Kai Fen [corrected to Cheng, Kai Fan].


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.

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