TY - JOUR
T1 - Amending HIV Drugs
T2 - A Novel Small-Molecule Approach to Target Lupus Anti-DNA Antibodies
AU - Vanpatten, Sonya
AU - Sun, Shan
AU - He, Mingzhu
AU - Cheng, Kai Fan
AU - Altiti, Ahmad
AU - Papatheodorou, Angelos
AU - Kowal, Czeslawa
AU - Jeganathan, Venkatesh
AU - Crawford, James M.
AU - Bloom, Ona
AU - Volpe, Bruce T.
AU - Grant, Christian
AU - Meurice, Nathalie
AU - Coleman, Thomas R.
AU - Diamond, Betty
AU - Al-Abed, Yousef
N1 - Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/10/13
Y1 - 2016/10/13
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.6b00694
DO - 10.1021/acs.jmedchem.6b00694
M3 - Article
C2 - 27603688
AN - SCOPUS:84991288347
SN - 0022-2623
VL - 59
SP - 8859
EP - 8867
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 19
ER -