Caelastrol and pristimerin derived from Leigongteng inhibit promoter activity of HLA-B*2705 gene

AIM: To screen the effective chemicals, which can suppress the promoter activity of the HLA-B*2705 gene as potential therapeutic agents. METHODS: The HeLa-HLA-B27, 293T-HLA-B27 stable transfectants were used to monitor the effect of 12 264 chemicals through high throughput screening (HTS). Chemicals which regulates HLA-B*2705 promoter activity more than 150% or less than 60% were picked out for the further IC50/EC50 and cell viability detection. RESULTS: (1) The primary screening used by 293T-HLA-B27 stable transfectant yielded about 5.1% hits which either suppressed (556 chemicals) or enhanced (68 chemicals) the HLA-B*2705 promoter activity. (2) A reconfirmation screening was carried out with these 624 of the candidates using transfected HeLa-HLA-B27 cells. Seventy hits were confirmed. (3) Based on the bioinformatics of those positive hits, 40 chemicals were selected for in-depth analysis by dose-response experiment and IC50/EC50 detection. Six suppressors showed potential pharmacological activities. Interestingly, two suppressors (celastrol and pristimerin) are derived from Leigongteng, a herbal medicine already used for several decades for treatment of immune regulatory and inflammatory diseases. Four active chemicals were computer designed with no relevance to the above structures. CONCLUSION: Chinese traditional herb Nansheteng and Leigongteng might be the potential drugs for HLA-B27 positive patients. These results provide new direction for research in both the therapeutics and the pathogenesis of spondyloarthritis.