Development of yeast-based high-throughput screening platform to screen for potential anti-HMG-CoA reductase compounds in Traditional Chinese Herbal Medicine
The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are commonly used for the treatment of dyslipidemia and prevention of coronary artery disease. Recently, preclinical studies have shown that HMG-CoA inhibitors may have chemopreventative and complementary chemotherapeutic effects in cancers . However, currently avaliable HMG-CoA inhibitiors still have some serious side effects, including transaminase elevation, myopathy and rhabdomyolysis. Based on Chinese medicine literature reviews there are quite a few of Traditional Chinese Herbal Medicines (TCM) which exhibit anti-hyperlipidemia effects. Recently, the interest in TCM drugs has tremendously increased due to the fact that they might potentially have fewer side effects. However, the major hurdle of the TCM drug discovery is that there are many of them and hundreds of thousands of chemical compounds available. In order to speed up the screening process, we have recently developed a reproducible, rapid and inexpensive yeast-based high-throughput screening (HTS) platform to identity potential HMG-CoA reductase inhibitors. Our screening assay is based on the fact that a HMG1 and HMG2 homozygous deletion strain is inviable in the absence of mevalonate . Therefore, we can use this genetic character of the yeast to screen for chemical compounds that inhibit HMG-CoA reductase. The HTS screening platform was tested using simvastatin (as a positive control), 14 different total extracts of herbs from TCM and 15 different fractions isolated thereof. The simvastatin, 6 total extracts and 3 isolated fractions suppressed the growth of deletion yeast cells but not its corresponding parental wild type strain, including Radix et Rhizoma Salviae miltiorrhizae, Radix et Rhizoma Rhei, Semen Cassiae, Rhizoma Curcumae longae, Herba Medyotidis, Flos Carthami and Gynostemma pentaphyllum. Taken together, these results demonstrate our platform as an economic and efficient HTS platform to identify novel HMG-CoA reductase inhibitors.
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