Shehzadi Kiran, Kalsoom Iqra, Yu Ming-Jia, Liang Jian-Hua
Key Laboratory of Medical Molecule Science and Pharmaceutical Engineering, Ministry of Industry and Information Technology, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, China.
J Biomol Struct Dyn. 2025 Feb 12:1-23. doi: 10.1080/07391102.2024.2335287.
The emergence of highly contagious SARS-CoV-2 variants emphasizes the need for antiviral drugs that can adapt to evolving viral mutations. Despite widespread vaccination efforts, novel variants and recurrence cases raise concerns about COVID-19. Although repurposed drugs like Remdesivir, a nucleoside inhibitor, offer treatment, there is still a critical need for alternative drugs. Inhibiting viral RdRp function remains a key strategy. Structural analysis highlights the importance of pyrrolo-triazine and pyrimidine scaffolds in nucleoside inhibitors. Our study designed Peptide Nucleic Acid (PNA) antisense pronucleotides by combining these scaffolds using structure-guided drug design. Molecular modeling, including molecular docking, pharmacokinetics, molecular dynamics simulations, and MMPBSA binding energy calculations, predicts that modified PNAs can disrupt ribosome assembly at the RdRp translation start site. The neutral backbone of PNAs may enhance sequence-specific RNA binding. MD simulations revealed that complexes of Remdesivir and L14 remained stable throughout, with the phosphate tail of L14 stabilized by a positive amino acid pocket near the RdRp-RNA entry channel, similar to Remdesivir. Additionally, L14's guanine motif interacted with U20, A19, and U18 on the primer RNA strand. The lead PNA analog (L14) showed superior binding free energy to both RdRp (-47.26 kcal/mol) and RdRp-RNA (-85.66 kcal/mol), outperforming Remdesivir. Key amino acid residues critical for binding affinity were identified, providing valuable insights for drug development. This promising PNA-mimetic compound offers dual-target specificity, presenting a compelling avenue for developing potent anti-SARS-CoV-2 agents.
高传染性的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）变体的出现凸显了对抗病毒药物的需求，这些药物需要能够适应不断演变的病毒突变。尽管进行了广泛的疫苗接种工作，但新变体和复发病例引发了人们对新冠肺炎的担忧。虽然像瑞德西韦这样的核苷抑制剂等重新利用的药物提供了治疗方法，但仍然迫切需要替代药物。抑制病毒RNA依赖性RNA聚合酶（RdRp）功能仍然是关键策略。结构分析突出了吡咯并三嗪和嘧啶支架在核苷抑制剂中的重要性。我们的研究通过使用结构导向药物设计结合这些支架来设计肽核酸（PNA）反义前体核苷酸。分子建模，包括分子对接、药代动力学、分子动力学模拟和MMPBSA结合能计算，预测修饰后的PNA可以在RdRp翻译起始位点破坏核糖体组装。PNA的中性骨架可能增强序列特异性RNA结合。分子动力学模拟显示，瑞德西韦和L14的复合物始终保持稳定，L14的磷酸尾巴通过RdRp-RNA进入通道附近的一个带正电荷的氨基酸口袋稳定，类似于瑞德西韦。此外，L14的鸟嘌呤基序与引物RNA链上的U20、A19和U18相互作用。先导PNA类似物（L14）对RdRp（-47.26千卡/摩尔）和RdRp-RNA（-85.66千卡/摩尔）均显示出优异的结合自由能，优于瑞德西韦。确定了对结合亲和力至关重要的关键氨基酸残基，为药物开发提供了有价值的见解。这种有前景的类PNA化合物具有双靶点特异性，为开发有效的抗SARS-CoV-2药物提供了一条引人注目的途径。
