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

• Published in: Journal of medicinal chemistry Vol. 59; no. 19; pp. 8859 - 8867
• Main Authors: VanPatten, Sonya, Sun, Shan, He, Mingzhu, Cheng, Kai Fan, Altiti, Ahmad, Papatheodorou, Angelos, Kowal, Czeslawa, Jeganathan, Venkatesh, Crawford, James M, Bloom, Ona, Volpe, Bruce T, Grant, Christian, Meurice, Nathalie, Coleman, Thomas R, Diamond, Betty, Al-Abed, Yousef
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 13-10-2016
• Subjects: Animals; Antibodies, Antinuclear - immunology; DNA - immunology; Drug Discovery; Female; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - pharmacokinetics; HIV Protease Inhibitors - pharmacology; HIV Protease Inhibitors - therapeutic use; Humans; Kidney Glomerulus - drug effects; Kidney Glomerulus - immunology; Kidney Glomerulus - pathology; Lupus Erythematosus, Systemic - drug therapy; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - pathology; Mice; Mice, Inbred NZB; Models, Molecular
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00694

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, 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.