Interaction of a small molecule Natura-α and STAT3-SH2 domain to block Y705 phosphorylation and inhibit lupus nephritis

• Published in: Biochemical pharmacology Vol. 99; pp. 123 - 131
• Main Authors: Chiao, J.W., Melikian, Maxime, Han, Liying, Xue, Chengsen, Tsao, Allen, Wang, Luxi, Mencher, Simon K., Fallon, John, Solangi, Karim, Bertho, Gildas, Wang, Long G.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01-01-2016; Elsevier
• Subjects: Amino Acid Sequence; Animals; Bioinformatics; Computational modeling; Computer Science; Female; Human health and pathology; Indoles - chemistry; Indoles - metabolism; Indoles - pharmacology; Inhibitor; Life Sciences; Lupus; Lupus Nephritis - metabolism; Mice; Mice, Inbred NZB; Molecular Sequence Data; NZB/W mice; Phosphorylation; Phosphorylation - drug effects; Phosphorylation - physiology; Protein Binding - physiology; Protein Structure, Tertiary; src Homology Domains - drug effects; src Homology Domains - physiology; STAT3; STAT3 Transcription Factor - chemistry; STAT3 Transcription Factor - metabolism; Lupus; Phosphorylation; Inhibitor; Computational modeling; NZB/W mice; STAT3
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2015.11.018

Natura-α binds SH2 domain of STAT3, forms H-bonds with Glu594 and Arg609, preventing Y705 phosphorylation. The efficacy was evaluated in lupus mice, Natura-α reduced proteinuria, glomerular lesion, and improved survival rate.
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A small molecule, Natura-α, a clinical stage investigational new drug for certain inflammatory diseases, has been evaluated for drug interaction with STAT3 and inhibiting systemic lupus erythematosus (SLE). Studies have revealed that it selectively inhibits STAT3-Y705 phosphorylation and, suppresses pro-inflammatory cytokines, stimulates anti-inflammatory cytokine IL-10, thereby skewing T cell differentiation from the Th1/Th17 lineages toward the Treg lineage. The potential binding of the drug to STAT3 protein has been investigated with a computational modeling and docking simulation using X-ray crystal structure of the STAT3β homodimer. Natura-α was shown to directly bind to SH2 domain of STAT3 and forms H-bonds with amino acids Glu594 and Arg609. The phosphorylation of Y705 was prevented and making the formation of STAT3 homodimer impossible, thereby blocking STAT3 activation. The in vivo efficacy of Natura-α in SLE was evaluated in a bioassay with NZB/W female mice. Mice at week 19 were given orally Natura-α at 25 or 75mg/kg, once a day, 5 days per week for 29 weeks. Mice were monitored weekly until 52 weeks of age. Both dosages were effective to reduce proteinuria and significantly improved animal survival rate. The renal functions were preserved with glomerular lesions reversed, which paralleled with decreased C3 deposit. The numbers of kidney cells stained with phosphorylated STAT3-Y705 remarkably decreased, demonstrating blocking of Y-705 phosphorylation by the treatment. Since NZB/W mice develop nephritis which resembles SLE in men, the data strongly suggests that Natura-α may be a potential effective therapeutic agent for lupus.