Generation of a unique small molecule peptidomimetic that neutralizes lupus autoantibody activity
Ona Bloom a,1, Kai Fen Cheng b,1, Mingzhu He b, Angelos Papatheodorou a, Bruce T. Volpec, Betty Diamond d,2,3,
and Yousef Al-Abed d,2,3
a Laboratory of Neuroimmunology, Autoimmune and Musculoskeletal Disease Center,
b Department of Medicinal Chemistry, Center for Biomedical Science, and
d Autoimmune and Musculoskeletal Disease Center, The Feinstein Institute for Medical Research, Manhasset, NY 11030; and
c Department of Neurology and Neuroscience, Burke Cornell Medical Research Institute, Weill Medical College of Cornell University, White Plains, NY 10605
Edited* by Jeffrey V. Ravetch, The Rockfeller University, New York, NY, and approved May 17, 2011 (received for review March 4, 2011)
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 speci?city are present in ˜40% of lupus patient sera and are both nephrotoxic and neurotoxic. Elevated titers are present in cerebrospinal ?uid of patients with central nervous system manifestations of SLE. Administration of the non-naturally 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.
www.pnas.org/cgi/doi/10.1073/pnas.1103555108 |
