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  3. Optimization, and biological evaluation of 3-O-β-chacotriosyl betulinic acid amide derivatives as novel small-molecule Omicron

Optimization, and biological evaluation of 3-O-β-chacotriosyl betulinic acid amide derivatives as novel small-molecule Omicron

  • Eur J Med Chem. 2023 Aug 5;256:115463. doi: 10.1016/j.ejmech.2023.115463.
Mingjian Liu 1,  Jinshen Wang 2,  Shanshan Shi 3,  Yongfeng Gao 1,  Yixiao Zhang 1,  Ziying Yuan 1,  Enlin Huang 1,  Sumei Li 4,  Shuwen Liu 5,  Gaopeng Song 6
Affiliations

Affiliations

  • 1 National Key Laboratory of Green Pesticide, 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 Department of Human Anatomy, College of Basic Medicine and Public Hygiene, Jinan University, Guangzhou, 510632, China. Electronic address: [email protected].
  • 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: [email protected].
  • 6 National Key Laboratory of Green Pesticide, College of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China. Electronic address: [email protected].
PMID: 37209612 DOI: 10.1016/j.ejmech.2023.115463
Abstract

SARS-CoV-2 Omicron viruses possess a high antigenic shift, and the approved anti-SARS-CoV-2 drugs are extremely limited, which makes the development of new Antiviral drugs for the clinical treatment and prevention of SARS-CoV-2 outbreaks imperative. We have previously discovered a new series of markedly potent small-molecule inhibitors of SARS-CoV-2 virus entry, exampled by the hit compound 2. Here, we report a further study of bioisosteric replacement of the eater linker at the C-17 position of 2 with a variety of aromatic amine moieties, followed by a focused structure-activity relationship study, leading to the discovery of a series of novel 3-O-β-chacotriosyl BA amide derivatives as small-molecule Omicron fusion inhibitors with improved potency and selectivity index. Particularly, our medicinal chemistry efforts have resulted in a potent, and efficacious lead compound S-10 with appreciable pharmacokinetic properties, which exhibited broad-spectrum potency against Omicron and other variants with EC50 values ranging from 0.82 to 5.45 μM. Mutagenesis studies confirmed that inhibition of Omicron viral entry was mediated by the direct interaction with S in the prefusion state. These results reveal that S-10 is suitable for further optimization as Omicron fusion inhibitors, with the potential to be developed as therapeutic agents for the treatment and control of SARS-CoV-2 ant its variants infections.

Keywords

3-O-β-chacotriosyl BA; Membrane fusion; Omicron; Structure-activity relationship.

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