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通过靶向刺突蛋白的融合前状态，鉴定、优化和生物评价 3-O-β-岩藻糖基熊果酸衍生物作为新型 SARS-CoV-2 进入抑制剂。

Identification, optimization, and biological evaluation of 3-O-β-chacotriosyl ursolic acid derivatives as novel SARS-CoV-2 entry inhibitors by targeting the prefusion state of spike protein.

机构信息

Key Laboratory for Biobased Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China.

Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.

出版信息

Eur J Med Chem. 2022 Aug 5;238:114426. doi: 10.1016/j.ejmech.2022.114426. Epub 2022 May 7.

DOI:10.1016/j.ejmech.2022.114426
PMID:35551037
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9076589/
Abstract

The COVID-19 pandemic generates a global threat to public health and continuously emerging SARS-CoV-2 variants bring a great challenge to the development of both vaccines and antiviral agents. In this study, we identified UA-18 and its optimized analog UA-30 via the hit-to-lead strategy as novel SARS-CoV-2 fusion inhibitors. The lead compound UA-30 showed potent antiviral activity against infectious SARS-CoV-2 (wuhan-HU-1 variant) in Vero-E6 cells and was also effective against infection of diverse pseudotyped SARS-CoV-2 variants with mutations in the S protein including the Omicron and Delta variants. More importantly, UA-30 might target the cavity between S1 and S2 subunits to stabilize the prefusion state of the SARS-CoV-2 S protein, thus leading to interfering with virus-cell membrane fusion. This study offers a set of novel SARS-CoV-2 fusion inhibitors against SARS-CoV-2 and its variants based on the 3-O-β-chacotriosyl UA skeleton.

摘要

新型 SARS-CoV-2 融合抑制剂的发现与优化

新型冠状病毒肺炎疫情的爆发对全球公共卫生构成了严重威胁，不断出现的 SARS-CoV-2 变异株给疫苗和抗病毒药物的研发带来了巨大挑战。本研究采用从命中到先导的策略，发现了新型 SARS-CoV-2 融合抑制剂 UA-18 及其优化类似物 UA-30。先导化合物 UA-30 对 Vero-E6 细胞中感染性 SARS-CoV-2（武汉-HU-1 变异株）具有很强的抗病毒活性，对包括奥密克戎和德尔塔变异株在内的 S 蛋白突变的多种假型 SARS-CoV-2 变异株的感染也具有有效性。更为重要的是，UA-30 可能靶向 S1 和 S2 亚基之间的腔，稳定 SARS-CoV-2 S 蛋白的预融合状态，从而干扰病毒-细胞膜融合。本研究基于 3-O-β-岩藻三糖 UA 骨架，提供了一系列针对 SARS-CoV-2 及其变异株的新型 SARS-CoV-2 融合抑制剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd30/9076589/0c2062441786/gr6_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd30/9076589/321fab2fe19c/ga1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd30/9076589/760e6a43cfd9/gr1a_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd30/9076589/1b90d0e360da/gr1b_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd30/9076589/0db4cbc44fd7/gr2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd30/9076589/fdac38e70ca5/gr3_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd30/9076589/ac76f0da78ca/sc1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd30/9076589/93354c63e258/gr4_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd30/9076589/9e0297a0cf3c/gr5_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd30/9076589/0c2062441786/gr6_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd30/9076589/321fab2fe19c/ga1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd30/9076589/760e6a43cfd9/gr1a_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd30/9076589/1b90d0e360da/gr1b_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd30/9076589/0db4cbc44fd7/gr2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd30/9076589/fdac38e70ca5/gr3_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd30/9076589/ac76f0da78ca/sc1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd30/9076589/93354c63e258/gr4_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd30/9076589/9e0297a0cf3c/gr5_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd30/9076589/0c2062441786/gr6_lrg.jpg

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