2. Academic Validation
  3. Assessing the inhibitory effects of some secondary amines, thioureas and 1,3-dimethyluracil conjugates of (-)-cytisine and thermopsine on the RNA-dependent RNA polymerase of SARS-CoV-1 and SARS-CoV-2

Assessing the inhibitory effects of some secondary amines, thioureas and 1,3-dimethyluracil conjugates of (-)-cytisine and thermopsine on the RNA-dependent RNA polymerase of SARS-CoV-1 and SARS-CoV-2

  • Bioorg Med Chem Lett. 2024 Sep 7:113:129950. doi: 10.1016/j.bmcl.2024.129950.
Yeh Chen 1,  Mann-Jen Hour 2,  Chen-Sheng Lin 3,  Young-Sheng Chang 4,  Zan-Yu Chen 5,  Alena V Koval'skaya 6,  Wen-Chi Su 7,  Inna P Tsypysheva 8,  Cheng-Wen Lin 9
Affiliations

Affiliations

  • 1 Department of Food Science and Biotechnology of National Chung Hsing University, Taichung, Taiwan.
  • 2 School of Pharmacy, China Medical University, Taichung 40402, Taiwan.
  • 3 Division of Gastroenterology, Kuang Tien General Hospital, No. 117, Shatian Rd, Shalu District, Taichung City 433, Taiwan.
  • 4 Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404394, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404394, Taiwan.
  • 5 Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404394, Taiwan.
  • 6 Ufa Institute of Chemistry, Ufa Federal Research Centre of the Russian Academy of Sciences, 71 prosp. Oktyabrya, 450054 Ufa, Russian Federation.
  • 7 Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404394, Taiwan; International Master's Program of Biomedical Sciences, China Medical University, Taichung 404394, Taiwan.
  • 8 Ufa Institute of Chemistry, Ufa Federal Research Centre of the Russian Academy of Sciences, 71 prosp. Oktyabrya, 450054 Ufa, Russian Federation. Electronic address: tsipisheva@anrb.ru.
  • 9 Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404394, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404394, Taiwan; Department of Medical Laboratory Science and Biotechnology, Asia University, Wufeng, Taichung 413305, Taiwan. Electronic address: cwlin@mail.cmu.edu.tw.
PMID: 39251111 DOI: 10.1016/j.bmcl.2024.129950
Abstract

SARS-CoV-2 causes COVID-19, with symptoms ranging from mild to severe, including pneumonia and death. This beta coronavirus has a 30-kilobase RNA genome and shares about 80 % of its nucleotide sequence with SARS-CoV-1. The replication/transcription complex, essential for viral RNA synthesis, includes RNA-dependent RNA polymerase (RdRp, nsp12) enhanced by nsp7 and nsp8. Antivirals like molnupiravir and remdesivir, which are RdRp inhibitors, treat severe COVID-19 but have limitations, highlighting the need for new therapies. This study assessed (-)-cytisine, methylcytisine, and thermopsine derivatives against SARS-CoV-1 and SARS-CoV-2 in vitro, focusing on their RdRp inhibition. Selected compounds from a previous study were evaluated using a SARS-CoV-2 RNA polymerase assay kit to investigate their structure-activity relationships. Compound 17 (1,3-dimethyluracil conjugate with (-)-cytisine and thermopsine) emerged as a potent inhibitor of SARS-CoV-1 and SARS-CoV-2 RdRp, with an IC50 value of 7.8 μM against SARS-CoV-2 RdRp. It showed a dose-dependent reduction in cytopathic effects in cells infected with SARS-CoV-1 and SARS-CoV-2 replicon-based single-round infectious particles (SRIPs) and significantly inhibited SARS-CoV N protein expression, with EC50 values of 0.12 µM for SARS-CoV-1 and 1.47 µM for SARS-CoV-2 SRIPs. Additionally, compound 17 reduced viral subgenomic RNA levels in a concentration-dependent manner in SRIP-infected cells. The structure-activity relationships of compound 17 with SARS-CoV-1 and SARS-CoV-2 RdRp were also investigated, highlighting it as a promising lead for developing Antiviral agents against SARS and COVID-19.

Keywords

1,3-Dimethyluracil; Cytisine; Inhibitor; RNA-dependent RNA polymerase; SARS-CoV-1; SARS-CoV-2; Thermopsine.

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