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.

Molecular and Functional Neuroscience in Immunity

“…This insight suggests new therapeutic possibilities. An interesting approach is antibody neutralization by using a decoy antigen to prevent antibody interactions with target tissues (192). A related question is whether cytokine-based or antibody-based therapies can be used in neuroprotective strategies (193) or for improving brain function (187).…”

Targeted silencing of DNA-specific B cells combined with partial plasma cell depletion displays additive effects on delaying disease onset in lupus-prone mice

“…However, twicemonthly Bz administration failed to prevent the immune response of lupus-prone mice to the antibody chimera. Resolving the problem of immunogenicity requires novel approaches [28]. For the last few decades CY has been the drug of choice for the treatment of lupus patients with renal involvement.…”

Maternal Anti-Fetal Brain IgG Autoantibodies and Autism Spectrum Disorder: Current Knowledge and its Implications for Potential Therapeutics

“…Defining the peptide epitopes recognized by maternal anti-brain autoantibodies will permit the generation of molecular mimeotpes, which share structural features with the peptide epitopes and can be orally absorbed by the mother[43, 44]. The peptide mimeotopes would act as a decoy antigens, competing with endogenous antigens expressed on the fetal brain[44].…”

“…These small molecule inhibitors could potentially neutralize the maternal autoantibodies and prevent antibody-mediated damage in the fetus(Figure 4). This technique is currently being explored as a therapy for antibody-mediated lupus brain disease[43, 44]. However, this therapy has not been tested in a pregnancy setting and due to the experimental nature of this treatment, the side effects are currently unknown.…”