Amending HIV Drugs: A Novel Small-Molecule Approach To Target Lupus Anti-DNA Antibodies.
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.
Sonya
S
VanPatten
Shan
S
Sun
Mingzhu
M
He
Kai Fan
KF
Cheng
Ahmad
A
Altiti
Angelos
A
Papatheodorou
Czeslawa
C
Kowal
Venkatesh
V
Jeganathan
James M
JM
Crawford
Ona
O
Bloom
Bruce T
BT
Volpe
BioMedical Research Models, Inc. , 67 Millbrook Street, Worcester, Massachusetts 01606, United States.
Christian
C
Grant
Department of Research, Mayo Clinic , 13400 East Shea Boulevard, Scottsdale, Arizona 85259, United States.
Nathalie
N
Meurice
Thomas R
TR
Coleman
Betty
B
Diamond
Yousef
Y
Al-Abed
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology*; D004247:DNA / Q000276:immunology; D055808:Drug Discovery; D005260:Female; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007678:Kidney Glomerulus / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008814:Mice, Inbred NZB; D008958:Models, Molecular
D000974:Antibodies, Antinuclear; D017320:HIV Protease Inhibitors; D004247:DNA