Discovery and structural optimization of 3-O-β-Chacotriosyl betulonic acid saponins as potent fusion inhibitors of Omicron virus infections

Mingjian Liu; Jinshen Wang; Xin Wan; Baixi Li; Mingming Guan; Xiaoyun Ning; Xiaojie Hu; Sumei Li; Shuwen Liu; Gaopeng Song

doi:10.1016/j.bioorg.2022.106316

Discovery and structural optimization of 3-O-β-Chacotriosyl betulonic acid saponins as potent fusion inhibitors of Omicron virus infections

Bioorg Chem. 2023 Feb:131:106316. doi: 10.1016/j.bioorg.2022.106316. Epub 2022 Dec 8.

Authors

Mingjian Liu¹, Jinshen Wang², Xin Wan³, Baixi Li¹, Mingming Guan¹, Xiaoyun Ning¹, Xiaojie Hu¹, Sumei Li⁴, Shuwen Liu⁵, Gaopeng Song⁶

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 Huizhou Health Sciences Polytechnic, Huizhou 516025, China.
⁴ Department of Human anatomy, School of Medicine, Jinan University, Guangzhou 510632, China. Electronic address: lisumei1234@163.com.
⁵ 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: liusw@smu.edu.cn.
⁶ 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: songgp1021@scau.edu.cn.

Abstract

The recent global Omicron epidemics underscore the great need for the development of small molecule therapeutics with appropriate mechanisms. The trimeric spike protein (S) of SARS-CoV-2 plays a pivotal role in mediating viral entry into host cells. We continued our efforts to develop small-molecule SARS-CoV-2 entry inhibitors. In this work, two sets of BA derivatives were designed and synthesized based on the hit BA-1 that was identified as a novel SARS-CoV-2 entry inhibitor. Compound BA-4, the most potent one, showed broad inhibitory activities against pOmicron and other pseudotyped variants with EC₅₀ values ranging 2.73 to 5.19 μM. Moreover, pSARS-CoV-2 assay, SPR analysis, Co-IP assay and the cell-cell fusion assay coupled with docking and mutagenesis studies revealed that BA-4 could stabilize S in the pre-fusion step to interfere with the membrane fusion, thereby displaying promising inhibition against Omicron entry.

Keywords: Betulonic acid derivatives; Membrane fusion; Omicron; Structure–activity relationships.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

COVID-19*
HIV Fusion Inhibitors*
Humans
Oleanolic Acid* / pharmacology
SARS-CoV-2
Saponins*
Virus Diseases*

Substances

betulonic acid
HIV Fusion Inhibitors
Oleanolic Acid
Saponins