更新于：2024-11-01

RdRp x DENV NS5 polymerase

更新于：2024-11-01

基本信息

关联

项与 RdRp x DENV NS5 polymerase 相关的药物

NITD-434

靶点

DENV NS5 polymerase x RdRp

作用机制

DENV NS5 polymerase抑制剂 [+1]

在研机构

Novartis Institutes for Biomedical Research, Inc.

原研机构

Novartis Institutes for Biomedical Research, Inc.

在研适应症

登革热

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 RdRp x DENV NS5 polymerase 相关的临床结果

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100 项与 RdRp x DENV NS5 polymerase 相关的转化医学

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0 项与 RdRp x DENV NS5 polymerase 相关的专利（医药）

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项与 RdRp x DENV NS5 polymerase 相关的文献（医药）

2023-10-01·European Journal of Medicinal Chemistry

Design, synthesis, and biological evaluation of a series of new anthraquinone derivatives as anti-ZIKV agents

Article

作者: Zhu, Yujia ; Long, Yuhua ; He, Zhenjian ; Liu, Wenbin ; Zhang, Bingzhi ; Zhu, Ge ; Yu, Jianchen ; Li, Junsen ; Chen, Tao ; Yuan, Jie ; Huang, Yun

The major severe complications linked to Zika virus (ZIKV) cause the global public health problems, including microcephaly and other congenital abnormalities in newborns, and Guillain-Barré syndrome, meningoencephalitis, multi-organ failure in adults. However, neither approved vaccines nor drugs are available for ZIKV. In this study, we describe the design, synthesis and the anti-ZIKV activities of a series of anthraquinone analogs. Most of the newly synthesized compounds demonstrated moderate to excellent potency against ZIKV. Among all, compound 22, showed the most potent anti-ZIKV activity (EC₅₀ value from 1.33 μM to 5.72 μM) with low cytotoxicity (CC₅₀＞50 μM) in multiple cellular model. Importantly, 22 significantly improved the survival of ZIKV-infected mice (Ifnar1^-/-), alleviated ZIKV-associated pathological damages and suppressed the excessive inflammatory response and pyroptosis induced by ZIKV in vivo and in vitro. Furthermore, the molecular docking simulation analysis and the surface plasmon resonance results demonstrated the direct binding between 22 and ZIKV RdRp, and the mechanistic study revealed that 22 suppressed viral RNA synthesis by ZIKV NS5 in cells. Taken together, this study highlights that 22 may be a novel anti-ZIKV drug candidate and provides treatment options for ZIKV-associated diseases.

2023-08-01·European Journal of Medicinal Chemistry

Perspectives on the current antiviral developments towards RNA-dependent RNA polymerase (RdRp) and methyltransferase (MTase) domains of dengue virus non-structural protein 5 (DENV-NS5)

Review

作者: Sreekanth, Gopinathan Pillai

A review.Dengue virus (DENV) infection is one of the most emerging arboviral infections in humans.DENV is a pos.-stranded RNA virus in the Flaviviridae family consisting of an 11 kb genome.DENV non-structural protein 5 (DENV-NS5) constitutes the largest among the non-structural proteins, which act as two domains, the RNA-dependent RNA polymerase (RdRp) and RNA methyltransferase enzyme (MTase).The DENV-NS5 RdRp domain contributes to the viral replication stages, whereas the MTase initiates viral RNA capping and facilitates polyprotein translation.Given the functions of both DENV-NS5 domains have made them an important druggable target.Possible therapeutic interventions and drug discoveries against DENV infection were thoroughly reviewed; however, a current update on the therapeutic strategies specific to DENV-NS5 or its active domains was not attempted.Since most potential compounds and drugs targeting the DENV-NS5 were evaluated in both in vitro cultures and animal models, a more detailed evaluation of mols./drug candidates still requires investigation in randomized controlled clin. trials.This review summarizes current perspectives on the therapeutic strategies adopted to target the DENV-NS5 (RdRp and MTase domains) at the host-pathogen interface and further discusses the directions to identify candidate drugs to combat DENV infection.

2023-06-01·Antiviral Research

Discovery of ZFD-10 of a pyridazino[4,5-b]indol-4(5H)-one derivative as an anti-ZIKV agent and a ZIKV NS5 RdRp inhibitor

Article

作者: Zhou, Guang-Feng ; Liu, Jinsong ; Qian, Weiyi ; Yang, Ren-Hua ; Li, Chun-Yan ; Gu, Xue-Rong ; Zheng, Chang-Bo ; Yang, Liu-Meng ; Xiong, Si-Dong ; Zhou, Guo-Chun ; Zheng, Yong-Tang ; Wang, Na ; Li, Feng

Zika virus (ZIKV) infection is associated with the birth defect microcephaly and Guillain-Barré syndrome in adults. There is no approved vaccine or specific antiviral agent against ZIKV. ZFD-10, a novel structural skeleton of 1H-pyridazino[4,5-b]indol-4(5H)-one, was firstly synthesized and discovered to be a potent anti-ZIKV inhibitor with very low cytotoxicity. ZFD-10's anti-ZIKV potency is independent of cell lines and ZFD-10 mainly targets the post-entry stages of ZIKV life cycle. Time-of-addition and time-of-withdrawal assays showed that 10 μM ZFD-10 displayed the ability to decrease mainly at the RNA level and weakly the viral progeny particle load. Furthermore, ZFD-10 could protect ZIKV NS5 from thermal unfolding and aggregation and increase the Tagg value of ZIKV NS5 protein from 44.6 to 49.3 °C, while ZFD-10 dose-dependently inhibits ZIKV NS5 RdRp activity using in vitro RNA polymerase assays. Molecular docking study suggests that ZFD-10 affects RdRp enzymatic function through interfering with the fingers and thumb subdomains. These results supported that ZFD-10's cell-based anti-ZIKV activity is related to its anti-RdRp activity of ZIKV NS5. The in vivo anti-ZIKV study shows that the middle-dose (4.77 mg/kg/d) of ZFD-10 protected mice from ZIKV infection and the viral loads of the blood, liver, kidney and brain in the middle-dose and high-dose (9.54 mg/kg/d) were significantly reduced compared to those of the ZIKV control. These results confirm that ZFD-10 has a certain antiviral effect against ZIKV infection in vivo.