研究解动力学和合成的单个同位素的胺酸-ProTide-Acyclovir
Thitiphong Khamkhenshorngphanuch1,2, Pitchayathida Mee-Udorn3, Maleeruk Utsintong4
1Thammasat University Research Unit in Drug, Health Product Development and Application (DHP-DA), Department of Pharmaceutical Sciences, Faculty of Pharmacy, Thammasat University, Pathum Thani 12120, Thailand.
ACS omega
|November 18, 2024
概括
研究人员合成了新型胺酸 - 酸 - 酸 (ACV) 异构体,以改善抗病毒治疗. 单个异构体对简单疹病毒 (HSV-1) 的疗效提高,其中一个异构体显著降低了病毒产量.
科学领域:
- 药用化学 医学化学
- 病毒学 病毒学
- 生物化学 生物化学
背景情况:
- 克洛维尔 (ACV) 是治疗简单疹 (HSV) 和疹-疹 (VZV) 感染的主要抗病毒药物,通过抑制病毒DNA聚合酶而起作用.
- 传统的ACV激活依赖于病毒胺基酶 (TK),对某些病毒菌株具有限制.
- 胺酸蛋白质提供了一个有前途的替代激活途径,绕过TK依赖.
研究的目的:
- 为了合成和表征胺酸的新型单异构体ProTide-ACV.
- 研究这些合成化合物的酶解水解动力学和机制.
- 评估新型ProTide-ACV异构体对简单疹病毒1型 (HSV-1) 的抗病毒疗效.
主要方法:
- 合成和分离的十二个新单异构体的胺酸蛋白质-ACV.
- 使用碳氧酶Y (CPY) 分析二聚体转化率的酶化水解动力学研究.
- 分子建模以阐明水解机制和固体阻碍效应.
- 对野生型HSV-1进行初步抗病毒查.
主要成果:
- 已成功合成并分离了单个胺酸的ProTide-ACV异构体.
- 酵素水解显示,与Sp-diastereomer相比,Rp-diastereomer的转化速度更快,对 tert-butyl 和 isopropyl 组观察到显著的固体阻碍.
- 在四个测试的单异构体中,有三种显示出相比于Acyclovir,对HSV-1的抗病毒疗效更强.
- 同位素24a在200μM度下显著降低HSV-1病毒产量.
结论:
- 将racemic ACV-ProTides分离成纯单异构体对于推进药物开发至关重要.
- 合成的胺酸和ProTide-ACV异构体显示出增强抗HSV活性的有希望的潜力.
- 了解水解动力学和硬化效应为设计下一代抗病毒药物的设计提供了宝贵的见解.
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