Development of N-Hydroxyindole-2-Carboxamides as New Host-Targeted Broad-Spectrum Antiviral Agents Against Human Respiratory Viruses

IF 7.3 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2026-10-12 DOI:10.1021/acs.jmedchem.6c01625

Giulia Bononi,Giulia Sibille,Erika Plicanti,Fabio Testori,Giusy L. Fratello,Arianna Maggiora,Iole Mannella,Stefano Sainas,Marta Giorgis,Donatella Boschi,Riccardo Miggiano,Miriana Di Stefano,Lisa Piazza,Carlotta Granchi,Giulio Poli,Tiziano Tuccinardi,Valeria Di Bussolo,Giulia Freer,Mauro Pistello,Davide M. Ferraris,Giorgio Gribaudo,Marco L. Lolli,Filippo Minutolo

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引用次数: 0

Abstract

Endoplasmic reticulum (ER) oxidoreductases are promising targets for host-targeted antiviral agents (HTAs) because of their essential role in protein folding, including the maturation of viral proteins. Human protein disulfide isomerase family member A3 (PDIA3) is involved in the folding of N-glycosylated client proteins, including viral envelope proteins, making it an attractive but underexplored antiviral target. Here, we describe the discovery of a novel N-hydroxyindole-2-carboxamide class of PDIA3 inhibitors, exemplified by compound AV22 (1o), which effectively inhibits PDIA3 activity and exerts broad-spectrum antiviral activity against major human respiratory viruses. Mechanistic studies indicated that AV22 (1o) increased the release of non-infectious coronavirus particles and reduced disulfide bond formation in the coronavirus spike protein, indicating that its antiviral effect stems from interference with PDIA3 activity. This new class of HTAs provides promising leads for drug discovery targeting viral envelope protein maturation vulnerabilities and is suitable for developing new BSAs.

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n -羟基吲哚-2-羧胺类新型宿主靶向广谱抗病毒药物的研究进展

内质网（ER）氧化还原酶是宿主靶向抗病毒药物（hta）的有希望的靶标，因为它们在蛋白质折叠中起重要作用，包括病毒蛋白质的成熟。人类蛋白二硫异构酶家族成员A3 （PDIA3）参与n -糖基化客户蛋白的折叠，包括病毒包膜蛋白，使其成为一个有吸引力但未被充分开发的抗病毒靶点。在这里，我们描述了一种新的n -羟基吲哚-2-羧酰胺类PDIA3抑制剂的发现，例如化合物AV22(10)，它能有效抑制PDIA3的活性，并对主要的人类呼吸道病毒具有广谱抗病毒活性。机制研究表明，AV22（10）增加了非感染性冠状病毒颗粒的释放，减少了冠状病毒刺突蛋白中二硫键的形成，表明其抗病毒作用源于干扰PDIA3活性。这类新的hta为针对病毒包膜蛋白成熟漏洞的药物发现提供了有希望的线索，并且适合开发新的bsa。

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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.