4-Iminooxazolidin-2-One as a Bioisostere of Cyanohydrin Suppresses EV71 Proliferation by Targeting 3C(pro).
4-Iminooxazolidin-2-One as a Bioisostere of Cyanohydrin Suppresses EV71 Proliferation by Targeting 3C(pro).
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4-Iminooxazolidin-2-One 作为氰醇的生物等排体通过靶向 3Cpro 抑制 EV71 增殖
DOI：
10.1128/spectrum.01025-21
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发表时间：
2021-12-22
影响因子：
3.7
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Xu B;Liu M;Ma S;Ma Y;Liu S;Shang L;Zhu C;Ye S;Wang Y
EV 71是手足口病最常见的病原体之一。到目前为止，还没有抗病毒药物可用于临床使用。摘要肠道病毒71型（EV 71）是引起手足口病（HFMD）的主要病原体，可导致严重的神经系统综合征。虽然迄今为止没有有效的临床药物可用于EV 71治疗，但EV 71 3C蛋白酶（3Cpro），一种由病毒编码的半胱氨酸蛋白酶，已经成为发现抗病毒药物的有希望的药物靶标，因为它在病毒增殖中起关键作用并干扰宿主细胞功能。在这里，我们报告了EV 71 3Cpro的两种抑制剂，FOPMC和FIOMC，它们是从先前报道的氰醇衍生物（R）-1通过用4-亚氨基恶唑烷-2-酮取代酰基氰醇基团而开发的。FOPMC和FIOMC具有有效的抗病毒活性和显著改善的代谢稳定性。这两种抑制剂对多种细胞系和五种流行病毒株表现出广泛的抗EV作用。通过分子对接和分子动力学模拟进一步阐明了3Cpro与FOPMC/FIOMC的结合模型。用4-亚氨基恶唑烷-2-酮取代酰基氰醇基团确实使FOPMC和FIOMC有效的抗EV 71药物候选物成为具有氰醇部分的通用非经典生物电子等排体。重要性EV 71是手足口病最流行的病原体之一。到目前为止，还没有抗病毒药物可用于临床使用。保守的EV 71 3Cpro在病毒增殖和防御宿主免疫中起关键作用，并且在宿主细胞中没有同源性，使其成为最有希望的抗病毒靶标。在这项工作中，我们确定了丙基和异丙基取代的4-亚氨基恶唑烷-2-酮部分（FOPMC和FIOMC）有效地抑制横纹肌肉瘤（RD），HEK-293 T和VeroE 6细胞系中的五种流行病毒株。通过分子对接和分子动力学模拟对抑制机理进行了初步探讨。不稳定的氰醇的成功替代大大改善了（R）-1的稳定性和药代动力学性质，使4-亚氨基恶唑烷-2-酮成为氰醇的非经典生物电子等排部分。这一发现解决了这些有前途的抗EV 71抑制剂的原始结构支架的关键问题，并可能导致它们作为广谱抗EV药物的开发。
EV71 is one of the most epidemic agents of HFMD. Thus far, there are no antiviral drugs available for clinical usage. ABSTRACT The fatal pathogen enterovirus 71 (EV71) is a major cause of hand-foot-and-mouth disease (HFMD), which leads to serious neurological syndromes. While there are no effective clinical agents available for EV71 treatment thus far, EV71 3C protease (3Cpro), a cysteine protease encoded by the virus, has become a promising drug target for discovery of antiviral drugs, given that it plays a crucial role in virus proliferation and interferes with host cell function. Here, we report two inhibitors of EV71 3Cpro, FOPMC and FIOMC, that were developed from previously reported cyanohydrin derivative (R)-1 by replacing the acyl cyanohydrin group with 4-iminooxazolidin-2-one. FOPMC and FIOMC have potent antiviral activity and dramatically improved metabolic stability. These two inhibitors demonstrated broad anti-EV effects on various cell lines and five epidemic viral strains. We further illuminated the binding models between 3Cpro and FOPMC/FIOMC through molecular docking and molecular dynamics simulations. The substitution of an acyl cyanohydrin group with 4-iminooxazolidin-2-one does make FOPMC and FIOMC potent anti-EV71 drug candidates as universal nonclassical bioisosteres with a cyanohydrin moiety. IMPORTANCE EV71 is one of the most epidemic agents of HFMD. Thus far, there are no antiviral drugs available for clinical usage. The conserved EV71 3Cpro plays pivotal roles in virus proliferation and defense host immunity, as well as having no homology in host cells, making it a most promising antiviral target. In this work, we identified that propyl- and isopropyl-substituted 4-iminooxazolidin-2-one moieties (FOPMC and FIOMC) effectively inhibited five epidemic viral strains in rhabdomyosarcoma (RD), HEK-293T, and VeroE6 cell lines. The inhibition mechanism was also illustrated with molecular docking and molecular dynamics (MD) simulations. The successful replacement of the labile cyanohydrin greatly improved the stability and pharmacokinetic properties of (R)-1, making 4-iminooxazolidin-2-one a nonclassical bioisosteric moiety of cyanohydrin. This discovery addressed a critical issue of the primitive structural scaffold of these promising anti-EV71 inhibitors and could lead to their development as broad-spectrum anti-EV agents.