Discovery of Indazole-Based Dual-Pharmacophore Inhibitors of Dengue and Zika Proteases as Promising Antivirals

IF 7.3 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2026-10-14 DOI:10.1021/acs.jmedchem.6c00523

Shubham K. Singh,Vijayarani Potluri,Surabhi Naza,Raveendra Madhukar Bhat,Poonam Patil,Hemavarshine M. S,Bhavita Kattula,Sarvalakshmi Pusarapu,Kalichamy Alagarasu,Rangappa S. Keri,Deepti Parashar,Anthony Addlagatta,Pragati K. Prasad

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引用次数: 0

Abstract

Abstract Flavivirus outbreaks caused by dengue virus (DENV) and Zika virus (ZIKV) remain a major global health challenge, with no FDA-approved antivirals available. Herein, we designed, synthesized, and evaluated indazole-based dual pharmacophore motifs targeting NS2B-NS3 serine proteases, essential for viral replication. Enzymatic assays revealed nanomolar to sub-micromolar potency, with strong selectivity over host serine proteases, minimizing off-target risks. Biophysical studies showed ligand-induced thermal stabilization, while kinetic and dialysis analyses confirmed a reversible, competitive, non-covalent inhibition mechanism. In DENV-infected Vero CCL-81 cells, several leads exhibited potent antiviral activity with low cytotoxicity. Notably, compound C8 demonstrated low-nanomolar enzyme inhibition against both viruses, translating to complete viral suppression in cells (EC50 = 0.5 μM) with a good selectivity index, underscoring its therapeutic potential. Molecular docking and molecular dynamics simulations supported these findings, revealing key active-site interactions consistent with potency and specificity. Collectively, these results highlight indazole-based dual-pharmacophore inhibitors as promising anti-flaviviral leads.

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以茚唑为基础的登革热和寨卡病毒蛋白酶双药效团抑制剂的发现

由登革热病毒（DENV）和寨卡病毒（ZIKV）引起的黄病毒疫情仍然是一个重大的全球卫生挑战，目前尚无fda批准的抗病毒药物可用。在此，我们设计、合成并评估了以茚唑为基础的靶向NS2B-NS3丝氨酸蛋白酶的双药效团基序，这是病毒复制所必需的。酶分析显示了纳摩尔到亚微摩尔的效力，对宿主丝氨酸蛋白酶具有很强的选择性，最大限度地降低了脱靶风险。生物物理研究表明配体诱导的热稳定，而动力学和透析分析证实了可逆的、竞争性的、非共价的抑制机制。在denv感染的Vero CCL-81细胞中，几种先导物表现出低细胞毒性的强抗病毒活性。值得注意的是，化合物C8对这两种病毒都表现出低纳摩尔酶抑制作用，在细胞中转化为完全的病毒抑制（EC50 = 0.5 μM），具有良好的选择性指数，强调了其治疗潜力。分子对接和分子动力学模拟支持了这些发现，揭示了与效力和特异性一致的关键活性位点相互作用。总的来说，这些结果突出了以茚唑为基础的双药效团抑制剂作为抗黄病毒先导物的前景。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.