Uricases as therapeutic agents to treat refractory gout: Current states and future directions.
Uricases as therapeutic agents to treat refractory gout: Current states and future directions.
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DOI：
10.1002/ddr.20493
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发表时间：
2012-03-01
影响因子：
3.8
通讯作者：
Liao, Fei
中科院分区：
文献类型：
--
作者：
Yang, Xiaolan;Yuan, Yonghua;Zhan, Chang-Guo;Liao, Fei
难治性痛风的治疗仍然是药物开发的一个挑战。虽然聚乙二醇化酶（一种用单甲氧基聚乙二醇 (mPEG) 修饰的重组哺乳动物尿酸酶）可有效治疗难治性痛风，但在以 0.14 毫克/千克体重的治疗剂量每两周一次持续治疗三个月后，它在近 20% 的患者中引发了针对 mPEG 的免疫反应。对于顽固性痛风的持续治疗，每月治疗剂量低于 4 μg/kg 体重的聚乙二醇化尿酸酶有希望。制定尿酸酶以实现每月一次的治疗方案需要药效学模拟和实验，包括：（a）基于合理设计和进化生物技术相结合的尿酸酶分子工程，以提高其固有的催化效率、热稳定性和对尿酸相对于黄嘌呤的选择性； (b)优化天然尿酸酶中可及的反应性氨基酸残基的数量和分布，以使用免疫原性低于mPEG的PEG衍生物进行位点特异性聚乙二醇化，以保留活性、最小化免疫原性并增强聚乙二醇化尿酸酶的药代动力学。对这些问题进行了简要回顾，作为刺激开发更安全的尿酸酶制剂以持续治疗难治性痛风的手段。
Treatment of refractory gout remains a challenge on drug development. While pegloticase, a recombinant mammalian uricase modified with monomethoxyl-poly(ethylene glycol) (mPEG) is effective in treating refractory gout, after continued treatment for three months biweekly at a therapeutic dose of 0.14 mg/kg body weight, it elicits an immune response against mPEG in nearly 20% of patients. For continued treatment of refractory gout PEGylated uricases at monthly therapeutic doses below 4 μg/kg body weight have promise. To formulate uricases to achieve monthly therapeutic regimens requires pharmacodynamics simulation and experimentation including: (a) molecular engineering of uricases based on rational design and evolution biotechnology in combination to improve their inherent catalytic efficiency, thermostability and selectivity for urate over xanthine and; (b) optimization of the number and distribution of accessible reactive amino acid residues in native uricases for site-specific PEGylation with PEG derivatives with lower of immunogenicity than mPEG to retain activity, minimize immunogenicity and enhance the pharmacokinetics of the PEGylated uricase. These issues are briefly reviewed as a means to stimulate the development of safer uricase formulations for continued treatment of refractory gout.
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影响因子：
3.6
作者：
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作者：
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