Development of a screening platform to discover natural products active against SARS-CoV-2 infection using lung organoid models.

IF 11.3 1区 医学 Q1 Medicine
Joo-Eun Lee, Se Yun Jeong, Zijun Li, Hyun-Yi Kim, Hyun-Woo Kim, Min Jeong Yoo, Hee Joo Jang, Do-Kyun Kim, Namki Cho, Hee Min Yoo, Ki Hyun Kim
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Abstract

Background: Natural products can serve as one of the alternatives, exhibiting high potential for the treatment and prevention of COVID-19, caused by SARS-CoV-2. Herein, we report a screening platform to test the antiviral efficacy of a natural product library against SARS-CoV-2 and verify their activity using lung organoids.

Methods: Since SARS-CoV-2 is classified as a risk group 3 pathogen, the drug screening assay must be performed in a biosafety level 3 (BSL-3) laboratory. To circumvent this limitation, pseudotyped viruses (PVs) have been developed as replacements for the live SARS-CoV-2. We developed PVs containing spikes from Delta and Omicron variants of SARS-CoV-2 and improved the infection in an angiotensin-converting enzyme 2 (ACE2)-dependent manner. Human induced pluripotent stem cells (hiPSCs) derived lung organoids were generated to test the SARS-CoV-2 therapeutic efficacy of natural products.

Results: Flavonoids from our natural product library had strong antiviral activity against the Delta- or Omicron-spike-containing PVs without affecting cell viability. We aimed to develop strategies to discover the dual function of either inhibiting infection at the beginning of the infection cycle or reducing spike stability following SARS-CoV-2 infection. When lung cells are already infected with the virus, the active flavonoids induced the degradation of the spike protein and exerted anti-inflammatory effects. Further experiments confirmed that the active flavonoids had strong antiviral activity in lung organoid models.

Conclusion: This screening platform will open new paths by providing a promising standard system for discovering novel drug leads against SARS-CoV-2 and help develop promising candidates for clinical investigation as potential therapeutics for COVID-19.

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开发筛选平台,利用肺器官模型发现对 SARS-CoV-2 感染有活性的天然产品。
背景:天然产物是治疗和预防由SARS-CoV-2引起的COVID-19的替代品之一,具有很高的潜力。在此,我们报告了一个筛选平台,以测试天然产品库对 SARS-CoV-2 的抗病毒功效,并使用肺器官组织验证其活性:方法:由于SARS-CoV-2被列为3类危险病原体,因此药物筛选试验必须在生物安全等级为3级(BSL-3)的实验室中进行。为了规避这一限制,人们开发了伪型病毒(PV)来替代活的 SARS-CoV-2。我们开发了含有 SARS-CoV-2 Delta 和 Omicron 变体尖峰的假病毒,并以血管紧张素转换酶 2 (ACE2) 依赖性方式改善了感染。为了测试天然产物对SARS-CoV-2的疗效,我们生成了人诱导多能干细胞(hiPSCs)衍生的肺器官组织:结果:我们的天然产品库中的黄酮类化合物对含有Delta或Omicron-spike的PV具有很强的抗病毒活性,且不影响细胞活力。我们的目标是制定策略,发现在感染周期开始时抑制感染或在感染 SARS-CoV-2 后降低尖峰稳定性的双重功能。当肺部细胞已经感染病毒时,活性黄酮类化合物会诱导尖峰蛋白降解,并发挥抗炎作用。进一步的实验证实,活性黄酮类化合物在肺器官模型中具有很强的抗病毒活性:这一筛选平台将为发现抗SARS-CoV-2的新药线索提供一个有前途的标准系统,从而开辟新的道路,并有助于开发有希望的候选药物,作为COVID-19的潜在治疗药物进行临床研究。
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
Biomaterials Research
Biomaterials Research Medicine-Medicine (miscellaneous)
CiteScore
10.20
自引率
3.50%
发文量
63
审稿时长
30 days
期刊介绍: Biomaterials Research, the official journal of the Korean Society for Biomaterials, is an open-access interdisciplinary publication that focuses on all aspects of biomaterials research. The journal covers a wide range of topics including novel biomaterials, advanced techniques for biomaterial synthesis and fabrication, and their application in biomedical fields. Specific areas of interest include functional biomaterials, drug and gene delivery systems, tissue engineering, nanomedicine, nano/micro-biotechnology, bio-imaging, regenerative medicine, medical devices, 3D printing, and stem cell research. By exploring these research areas, Biomaterials Research aims to provide valuable insights and promote advancements in the biomaterials field.
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