HWY-289, a novel semi-synthetic protoberberine derivative with multiple target sites in Candida albicans
HWY-289, a novel semi-synthetic protoberberine derivative with multiple target sites in Candida albicans
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DOI：
10.1093/jac/47.5.513
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发表时间：
2001-05-01
影响因子：
5.2
通讯作者：
Paik, YK
中科院分区：
文献类型：
--
作者：
Park, KS;Kang, KC;Paik, YK
研究了 515 种合成和半合成原小檗碱的抗真菌特性。选择 HWY-289 进行进一步研究是因为它表现出最显着的抗念珠菌活性（白色念珠菌和克柔念珠菌的 MIC 为 1.56 mg/L；吉里蒙念珠菌的 MIC 为 6.25 mg/L），但在大鼠中没有表现出毒性。 HWY-289抑制白色念珠菌全细胞中L-[甲基-C-14]甲硫氨酸掺入麦角甾醇的C-24中(IC50 20 muM)。然而，HWY-289 (100 muM) 对大鼠微粒体中的哺乳动物胆固醇生物合成没有影响，而咪康唑 (100 muM) 在相同的测定条件下是胆固醇生物合成的有效抑制剂。 HWY-289 的第二个主要靶位点涉及白色念珠菌的细胞壁生物合成，HWY-289 是几丁质合酶同工酶 CaCHS1 和 CaCHS2 的有效抑制剂，每种酶的 IC50 值为 22 muM。该效果具有高度特异性，因为HWY-289对白色念珠菌CaCHS3没有显着影响（IC50>200μM）。因此，HWY-289作为体外念珠菌生长抑制剂，与成熟的抗真菌药物相比，具有相当大的潜力，并且作为一类对人类宿主无毒副作用的新型抗真菌药物具有相当大的潜力。
The antifungal properties of 515 synthetic and semi-synthetic protoberberines were investigated. HWY-289 was chosen for further study because it exhibited the most significant anti-Candida activity (MICs were 1.56 mg/L for Candida albicans and Candida krusei; 6.25 mg/L for Candida guilliermondii) but did not demonstrate toxicity in rats. HWY-289 inhibited the incorporation of L-[methyl-C-14]methionine into the C-24 of ergosterol in whole cells of C. albicans (IC50 20 muM). However, HWY-289 (100 muM) had no effect on mammalian cholesterol biosynthesis in rat microsomes while miconazole (100 muM) was a potent inhibitor of cholesterol biosynthesis under identical assay conditions. A second major target site for HWY-289 was identified that involves cell wall biosynthesis in C. albicans, HWY-289 was a potent inhibitor of the chitin synthase isozymes CaCHS1 and CaCHS2, with IC50 values of 22 muM for each enzyme. The effect was highly specific in that HWY-289 had no significant effect on C, albicans CaCHS3 (IC50 > 200 muM). Thus, HWY-289 compared favourably with well-established antifungal agents as an inhibitor of the growth of Candida species in vitro, and may have considerable potential as a new class of antifungal agent that lacks toxic side effects in the human host.