Amending HIV Drugs: A Novel Small-Molecule Approach to Target Lupus Anti-DNA Antibodies

Sonya Vanpatten, Shan Sun, Mingzhu He, Kai Fan Cheng, Ahmad Altiti, Angelos Papatheodorou, Czeslawa Kowal, Venkatesh Jeganathan, James M. Crawford, Ona Bloom, Bruce T. Volpe, Christian Grant, Nathalie Meurice, Thomas R. Coleman, Betty Diamond, Yousef Al-Abed

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Systemic lupus erythematosus is an autoimmune disease that can affect numerous tissues and is characterized by the production of nuclear antigen-directed autoantibodies (e.g., anti-dsDNA). Using a combination of virtual and ELISA-based screens, we made the intriguing discovery that several HIV-protease inhibitors can function as decoy antigens to specifically inhibit the binding of anti-dsDNA antibodies to target antigens such as dsDNA and pentapeptide DWEYS. Computational modeling revealed that HIV-protease inhibitors comprised structural features present in DWEYS and predicted that analogues containing more flexible backbones would possess preferred binding characteristics. To address this, we reduced the internal amide backbone to improve flexibility, producing new small-molecule decoy antigens, which neutralize anti-dsDNA antibodies in vitro, in situ, and in vivo. Pharmacokinetic and SLE model studies demonstrated that peptidomimetic FISLE-412,1 a reduced HIV protease inhibitor analogue, was well-tolerated, altered serum reactivity to DWEYS, reduced glomeruli IgG deposition, preserved kidney histology, and delayed SLE onset in NZB/W F1 mice.

Original languageEnglish (US)
Pages (from-to)8859-8867
Number of pages9
JournalJournal of Medicinal Chemistry
Volume59
Issue number19
DOIs
StatePublished - Oct 13 2016

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Vanpatten, S., Sun, S., He, M., Cheng, K. F., Altiti, A., Papatheodorou, A., Kowal, C., Jeganathan, V., Crawford, J. M., Bloom, O., Volpe, B. T., Grant, C., Meurice, N., Coleman, T. R., Diamond, B., & Al-Abed, Y. (2016). Amending HIV Drugs: A Novel Small-Molecule Approach to Target Lupus Anti-DNA Antibodies. Journal of Medicinal Chemistry, 59(19), 8859-8867. https://doi.org/10.1021/acs.jmedchem.6b00694