防止导尿管堵塞的新型尿素酶抑制剂的合理设计和体外测试

IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Rachel A. Heylen, Nicola Cusick, Tom White, Emily J. Owen, Bethany L. Patenall, Martin Alm, Peter Thomsen, Maisem Laabei and A. Toby A. Jenkins
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引用次数: 0

摘要

由尿素酶阳性微生物引起的导尿管相关性尿路感染(CAUTI)可导致导尿管堵塞:尿素酶将尿液中的尿素代谢为氨,导致 pH 值升高,从而使导尿管管腔和膀胱中的结石和磷灰石盐沉淀,导致堵塞。乙酰羟肟酸(AHA)是目前唯一获准用于患者的尿素酶抑制剂,但由于其副作用而很少使用。在此,我们报告了利用合理的硅学药物设计方法鉴定和开发新脲酶抑制剂的情况。我们设计了一系列化合物,并对这些化合物进行了筛选和过滤,最终确定了三个化合物,并对其进行了体外脲酶活性测试。N,N′-双(3-吡啶基甲基)硫脲(Bis-TU)在活性测定中的表现优于 AHA,并在体外膀胱模型中进行了测试,与 AHA 相比,它显著延长了导管的使用寿命。Bis-TU 通过可扩散的球囊导管直接输送到活动部位,从而实现了局部给药。通过这种经济有效的药物设计方法,我们鉴定出了一种强效尿素酶抑制剂,并可通过反复重复该方法对其进行改进,设计过程还可用于针对其他疾病的治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Rational design and in vitro testing of new urease inhibitors to prevent urinary catheter blockage†

Rational design and in vitro testing of new urease inhibitors to prevent urinary catheter blockage†

Rational design and in vitro testing of new urease inhibitors to prevent urinary catheter blockage†

Catheter associated urinary tract infections (CAUTI) caused by urease-positive organisms can lead to catheter blockage: urease metabolizes urea in urine to ammonia causing an increase in pH and hence precipitation of struvite and apatite salts into the catheter lumen and bladder leading to blockage. Acetohydroxamic acid (AHA) is the only urease inhibitor currently approved for patient use, however, it is rarely used owing to its side effects. Here, we report the identification and development of new urease inhibitors discovered using a rational in silico drug design approach. A series of compounds were designed, the compounds were screened and filtered to identify three compounds which were tested in in vitro urease activity assays. N,N′-Bis(3-pyridinylmethyl)thiourea (Bis-TU) outperformed AHA in activity assays and was tested in an in vitro bladder model, where it significantly extended the lifetime of the catheter compared to AHA. Bis-TU was delivered via a diffusible balloon catheter directly to the site of activity, thus demonstrating localized drug delivery. This cost-effective drug design approach allowed the identification of a potent urease inhibitor, which could be improved through iterative repeats of the method, and the process of design could be utilized to target other diseases.

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CiteScore
5.80
自引率
2.40%
发文量
129
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