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

Hui Li; Chen Cheng; Shanshan Shi; Yan Wu; Yongfeng Gao; Zhihao Liu; Mingjian Liu; Zhaodong Li; Lijian Huo; Xiaoyan Pan; Shuwen Liu; Gaopeng Song

doi:10.1016/j.ejmech.2022.114426

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

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

Authors

Hui Li¹, Chen Cheng², Shanshan Shi³, Yan Wu⁴, Yongfeng Gao¹, Zhihao Liu¹, Mingjian Liu¹, Zhaodong Li¹, Lijian Huo¹, Xiaoyan Pan⁵, Shuwen Liu⁶, Gaopeng Song⁷

Affiliations

¹ Key Laboratory for Biobased Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China.
² Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
³ Department of Microbiology and Immunology, College of Basic Medicine and Public Hygiene, Jinan University, Guangzhou, 510632, China.
⁴ State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.
⁵ State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China. Electronic address: [email protected].
⁶ Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China; State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, Guangzhou, 510515, China. Electronic address: [email protected].
⁷ Key Laboratory for Biobased Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China. Electronic address: [email protected].

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.

Keywords: Membrane fusion; Pentacyclic triterpenoid saponins; SARS-CoV-2; SARs.

MeSH terms

Antiviral Agents* / pharmacology
COVID-19 Drug Treatment*
Humans
SARS-CoV-2* / drug effects
SARS-CoV-2* / physiology
Spike Glycoprotein, Coronavirus* / antagonists & inhibitors
Triterpenes* / pharmacology
Ursolic Acid
Virus Internalization* / drug effects

Substances

Antiviral Agents
Spike Glycoprotein, Coronavirus
Triterpenes
spike protein, SARS-CoV-2

Supplementary concepts

SARS-CoV-2 variants