School of Life Sciences, Tianjin Universitygrid.33763.32, Tianjin, People's Republic of China.
Department of Chemistry, Texas A&M University, College Station, Texas, USA.
Microbiol Spectr. 2021 Dec 22;9(3):e0102521. doi: 10.1128/Spectrum.01025-21. Epub 2021 Nov 17.
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 (3C), 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 3C, FOPMC and FIOMC, that were developed from previously reported cyanohydrin derivative ()-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 3C 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. EV71 is one of the most epidemic agents of HFMD. Thus far, there are no antiviral drugs available for clinical usage. The conserved EV71 3C 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 ()-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.
肠道病毒 71 型（EV71）是手足口病（HFMD）的主要病原体，可导致严重的神经系统综合征。目前尚无有效的临床药物可用于 EV71 治疗，但病毒编码的 3C 蛋白酶（3C）已成为发现抗病毒药物的有希望的药物靶点，因为它在病毒增殖中起着至关重要的作用，并干扰宿主细胞功能。在这里，我们报告了两种 EV71 3C 的抑制剂 FOPMC 和 FIOMC，它们是通过用 4-亚氨基恶唑烷-2-酮取代先前报道的氰醇衍生物（）-1 中的酰基氰醇基团而开发的。FOPMC 和 FIOMC 具有很强的抗病毒活性和显著提高的代谢稳定性。这两种抑制剂对各种细胞系和五种流行病毒株均表现出广泛的抗 EV 作用。我们进一步通过分子对接和分子动力学模拟阐明了 3C 与 FOPMC/FIOMC 之间的结合模型。用 4-亚氨基恶唑烷-2-酮取代酰基氰醇基团使 FOPMC 和 FIOMC 成为具有氰醇部分的通用非经典生物等排体，成为强效抗 EV71 药物候选物。EV71 是手足口病最流行的病原体之一。迄今为止，尚无抗病毒药物可供临床使用。保守的 EV71 3C 在病毒增殖和防御宿主免疫中起着关键作用，并且在宿主细胞中没有同源性，使其成为最有前途的抗病毒靶标。在这项工作中，我们发现丙基和异丙基取代的 4-亚氨基恶唑烷-2-酮部分（FOPMC 和 FIOMC）可有效抑制横纹肌肉瘤（RD）、HEK-293T 和 VeroE6 细胞系中的五种流行病毒株。抑制机制也通过分子对接和分子动力学（MD）模拟进行了说明。不稳定氰醇的成功替代大大提高了（）-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等排体。这一发现解决了这些有前途的抗 EV71 抑制剂原始结构支架的关键问题，并可能导致它们作为广谱抗 EV 药物的发展。
