Bernardini Giulia, Trezza Alfonso, Petricci Elena, Romagnoli Giulia, Zambardino Demetra, Manetti Fabrizio, Braconi Daniela, Geminiani Michela, Santucci Annalisa
ONE-HEALTH Lab, Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro, 53100 Siena, Italy.
MetabERN, Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro, 53100 Siena, Italy.
Int J Mol Sci. 2025 Mar 29;26(7):3181. doi: 10.3390/ijms26073181.
Alkaptonuria (AKU) is an ultra-rare genetic disorder caused by mutations in the homogentisate 1,2-dioxygenase () gene, leading to the accumulation of homogentisic acid (HGA). Current treatment options are limited, with Nitisinone (Orfadin or NTBC) being the only approved drug. However, its long-term use raises concerns due to significant adverse effects, highlighting the urgent need for safer alternatives. AKU manifests with progressive and often painful symptoms, severely impacting patients' quality of life. Identifying new therapeutic approaches to inhibit 4-hydroxyphenyl pyruvate dioxygenase (4-HPPD) is critical to improving outcomes for AKU patients. In this study, we present a novel integrated in vitro and in silico strategy to assess the residence time of 4-HPPD inhibitors. In particular, we evaluated several features of a set of triketone compounds including their inhibitory efficacy, residence time, and ochronotic pigment accumulation. By means of our integrated approach, we investigated the pharmacokinetic and pharmacodynamics properties of novel 4-HPPD inhibitors and provided a promising foundation for the development of safer and more effective treatments for AKU.
黑尿症（AKU）是一种极为罕见的遗传性疾病，由尿黑酸1,2-双加氧酶（）基因突变引起，导致尿黑酸（HGA）蓄积。目前的治疗选择有限，尼替西农（奥法迪恩或NTBC）是唯一获批的药物。然而，由于其显著的不良反应，长期使用引发了担忧，凸显了对更安全替代药物的迫切需求。AKU表现为进行性且常伴有疼痛的症状，严重影响患者的生活质量。确定抑制4-羟基苯丙酮酸双加氧酶（4-HPPD）的新治疗方法对于改善AKU患者的治疗效果至关重要。在本研究中，我们提出了一种新颖的体外和计算机模拟相结合的策略，以评估4-HPPD抑制剂的驻留时间。特别是，我们评估了一组三酮化合物的几个特性，包括它们的抑制效果、驻留时间和褐黄病色素积累。通过我们的综合方法，我们研究了新型4-HPPD抑制剂的药代动力学和药效学特性，并为开发更安全、更有效的AKU治疗方法提供了有前景的基础。
