This proposal focuses on the development of a new therapeutic for systemic lupus erythematosus. The overall goal is to 1) modify a peptide mimetope of DNA to increase serum half life, permit oral administration, and maximize function, 2) to explore the functionality of two new compounds with similar binding properties to the peptide and 3) develop additional compounds. The mimetope binds to a subset of anti-DNA antibodies that deposit in glomeruli, cross-react with NMDA receptors and mediate excitotoxic neuron death, and, in immune complexes, activate dendritic cells. Efforts will be made to use radioisotope-tagged peptide/modified compound to ablate antigen-specific B cells. It will also be determined if peptide intercalates into DNA-containing immune complexes to diminish activation of dendritic cells. Finally, new peptide mimetopes of DNA will be sought in case more than one subset of anti-DNA antibodies or DNA-reactive B cells must be eliminated to reduce disease pathology.

Public Health Relevance

This proposal identifies a non-immunosuppressive strategy for the treatment of systemic lupus.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Mancini, Marie
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Feinstein Institute for Medical Research
United States
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Altiti, Ahmad S; Cheng, Kai Fan; He, Mingzhu et al. (2017) ?-Hydroxy-tetrahydroquinolines from Quinolines Using Chloroborane: Synthesis of the Peptidomimetic FISLE-412. Chemistry 23:10738-10743
Son, Myoungsun; Porat, Amit; He, Mingzhu et al. (2016) C1q and HMGB1 reciprocally regulate human macrophage polarization. Blood 128:2218-2228
Son, Myoungsun; Kim, Sun Jung; Diamond, Betty (2016) SLE-associated risk factors affect DC function. Immunol Rev 269:100-17
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VanPatten, Sonya; Sun, Shan; He, Mingzhu et al. (2016) Amending HIV Drugs: A Novel Small-Molecule Approach To Target Lupus Anti-DNA Antibodies. J Med Chem 59:8859-8867
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Suurmond, Jolien; Diamond, Betty (2015) Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity. J Clin Invest 125:2194-202
Son, Myoungsun; Diamond, Betty (2015) C1q-mediated repression of human monocytes is regulated by leukocyte-associated Ig-like receptor 1 (LAIR-1). Mol Med 20:559-68
Bloom, Ona; Cheng, Kai Fan; Cheng, Kai Fen et al. (2011) Generation of a unique small molecule peptidomimetic that neutralizes lupus autoantibody activity. Proc Natl Acad Sci U S A 108:10255-9

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