Uricase formulated with polyethylene glycol (uricase-PEG 20): biochemical rationale and preclinical studies.
Uricase formulated with polyethylene glycol (uricase-PEG 20): biochemical rationale and preclinical studies.
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发表时间：
2002-09
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通讯作者：
J. Bomalaski;Frederick W. Holtsberg;C. Ensor;M. A. Clark
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作者：
J. Bomalaski;Frederick W. Holtsberg;C. Ensor;M. A. Clark
目的人类尿酸氧化酶开放阅读框5 ′端插入一个无义密码子，表达该酶的一个无酶活性片段，因此不能将尿酸代谢为尿囊素，易发生高尿酸血症和痛风。来自哺乳动物和微生物的各种尿酸氧化酶（尿酸酶）已被给予患有高尿酸血症和痛风的人。尽管这些疗法在降低血浆尿酸方面是成功的，但由于所用酶的不良生物化学性质、短的循环半衰期和这些制剂的固有抗原性，这些疗法的应用有限。方法：我们比较了尿酸氧化酶从各种来源的比酶活性，pH值的最佳值，亲和力，并保留酶活性在生理条件下。测试了多种聚乙二醇（PEG）以配制尿酸酶。结果产朊假丝酵母的尿酸氧化酶具有更好的酶学性质，分子量为20，000的聚乙二醇（称为尿酸酶-PEG 20）的抗原性大大降低，循环半衰期增加。结论尿酸酶-PEG 20可用于治疗高尿酸血症和痛风。
OBJECTIVE Humans have a non-sense codon inserted into the 5 prime end of the open reading frame of urate oxidase, and thus express an enzymatically inactive fragment of this enzyme; and consequently are unable to metabolize uric acid into allantoin and are prone to develop hyperuricemia and gout. Various urate oxidases (uricase) from mammals and microorganisms have been administered to humans with hyperuricemia and gout. Although successful in lowering plasma uric acid, these therapies have had limited application due to undesirable biochemical properties of the enzymes used, the short circulating half-life, and inherent antigenicity of these preparations. METHODS We compared urate oxidase from a variety of sources for specific enzyme activity, pH optimum, affinity, and retention of enzyme activity under physiological conditions. A variety of polyethylene glycols (PEG) were tested to formulate uricase. RESULTS Urate oxidase from Candida utilis had more favorable enzymatic properties and PEG of 20,000 MW (termed uricase-PEG 20) had greatly reduced antigenicity and increased circulating half-life as compared to those previously described. CONCLUSION It is anticipated that uricase-PEG 20 may have utility as a treatment for hyperuricemia and gout.