Inhibition of para-Hydroxyphenylpyruvate Dioxygenase by Analogues of the Herbicide Nitisinone As a Strategy to Decrease Homogentisic Acid Levels, the Causative Agent of Alkaptonuria

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• 作者：Dr. Marcella Laschi ; Dr. Giulia Bernardini ; Dr. Elena Dreassi ; Dr. Lia Millucci ; Dr. Michela Geminiani ; Dr. Daniela Braconi ; Dr. Barbara Marzocchi ; Prof. Maurizio Botta ; Prof. Fabrizio Manetti and Prof. Dr. Annalisa Santucci
• 关键词：alkaptonuria ; enzymes ; inhibitors ; nitisinone ; p-hydroxyphenylpyruvate dioxygenase
• 刊名：ChemMedChem
• 出版年：2016
• 出版时间：April 5, 2016
• 年：2016
• 卷：11
• 期：7
• 页码：674-678
• 全文大小：997K
• ISSN：1860-7187

文摘

Alkaptonuria (AKU) is a rare multisystem metabolic disease caused by deficient activity of homogentisate 1,2-dioxygenase (HGD), which leads to the accumulation of homogentisic acid (HGA). Currently, there is no treatment for AKU. The sole drug with some beneficial effects is the herbicide nitisinone (1), an inhibitor of p-hydroxyphenylpyruvate dioxygenase (4-HPPD). 1 has been used as a life-saving drug in infants with type I tyrosinemia despite severe side effects due to the buildup of tyrosine. Four clinical trials of nitisinone to treat AKU have shown that 1 consistently decreases HGA levels, but also caused the accumulation of tyrosine in blood serum. Moreover, the human preclinical toxicological data for 1 are incomplete. In this work, we performed pharmacodynamics and toxicological evaluations of 1, providing the first report of LD₅₀ values in human cells. Intracellular tyrosinemia was also evaluated. Three additional 4-HPPD inhibitors with a more favorable profile than that of 1 in terms of IC₅₀, LD₅₀, and tyrosine accumulation were also identified among commercially available compounds. These may be promising starting points for the development of new therapeutic strategies for the treatment of AKU.