Harnessing Natural Products by a Pharmacophore-Oriented Semisynthesis Approach for the Discovery of Potential Anti-SARS-CoV-2 Agents.
Yuan-Fei ZhouBing-Chao YanQian YangXin-Yan LongDan-Qi ZhangRong-Hua LuoHan-Yu WangHan-Dong SunXiao-Song XueYong-Tang ZhengPema-Tenzin PunoPublished in: Angewandte Chemie (International ed. in English) (2022)
Natural products possessing unique scaffolds may have antiviral activity but their complex structures hinder facile synthesis. A pharmacophore-oriented semisynthesis approach was applied to (-)-maoelactone A (1) and oridonin (2) for the discovery of anti-SARS-CoV-2 agents. The Wolff rearrangement/lactonization cascade (WRLC) reaction was developed to construct the unprecedented maoelactone-type scaffold during semisynthesis of 1. Further mechanistic study suggested a concerted mechanism for Wolff rearrangement and a water-assisted stepwise process for lactonization. The WRLC reaction then enabled the creation of a novel family by assembly of the maoelactone-type scaffold and the pharmacophore of 2, whereby one derivative inhibited SARS-CoV-2 replication in HPA EpiC cells with a low EC 50 value (19±1 nM) and a high TI value (>1000), both values better than those of remdesivir.
Keyphrases
- sars cov
- molecular docking
- molecular dynamics
- tissue engineering
- respiratory syndrome coronavirus
- small molecule
- induced apoptosis
- high throughput
- cell cycle arrest
- photodynamic therapy
- high resolution
- big data
- signaling pathway
- climate change
- risk assessment
- machine learning
- deep learning
- cell proliferation
- electron transfer
- coronavirus disease