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一种对外核酶耐药的链终结核酸模拟物,向SARS-CoV-2复制酶复合体

Ashleigh Shannon¹, Aurélie Chazot¹, Mikael Feracci¹

¹AFMB, CNRS, Aix-Marseille University, UMR 7257, Case 925, 163 Avenue de Luminy, 13288, Marseille Cedex 09, France.

Nucleic acids research

|December 14, 2023

概括

一种新型核酸模拟物,AT-9052,通过抵抗病毒外核酶去除,克服了冠状病毒耐药性. 它的Sp同位素可以选择性地抑制病毒RNA合成,提供针对SARS-CoV-2和其他病毒感染的新策略.

科学领域:

病毒学病毒学
药用化学医学化学
分子生物学分子生物学

背景情况:

核酸类似物 (NA) 是关键的抗病毒药物,包括COVID-19.
冠状病毒具有校对外核酶 (nsp14/nsp10),可以去除NA,从而限制其有效性.
贝米尼福斯布维尔 (AT-9010) 是一种用于抗击SARS-CoV-2的NA,但易受这种抗药机制的影响.

研究的目的:

开发一种抗冠状病毒外核酶介导抗性的新型核酸模拟物.
为了研究修改后的类似物AT-9052.的作用机制和疗效.

主要方法:

贝米尼福斯布维尔的化学修饰,以制造一个α-thiophosphate类似物 (AT-9052).
同结晶研究以确定基质偏好和结合相互作用.
在体外活性测试使用核酸二酸激酶 (NDPK) 和SARS-CoV-2RNA聚合酶 (nsp12).
使用病毒外核酶复合体 (nsp14/nsp10) 的切除试验.

主要成果:

该α-thiophosphate修改使得NA具有抗 nsp14/nsp10外核酶的切除能力.
AT-9052的Sp epimer被NDPK和SARS-CoV-2 nsp12首选使用.
通过nsp12将AT-9052-Sp纳入,导致链条立即终结,并且可以抵抗随后的切除.
与AT-9010不同的是,AT-9052-Sp没有抑制nsp12的N端核化域,而AT-9010.

结论:

AT-9052-Sp证明了针对SARS-CoV-2的新型作用机制,逃避病毒抵抗.
基修饰代表了一种提高对抗性病毒的NA疗效的总体策略.
这种方法可以应用于拯救因冠状病毒校对机制而受到阻碍的现有NA.

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