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  3. Inhibition of dengue viruses by N-methylcytisine thio derivatives through targeting viral envelope protein and NS2B-NS3 protease

Inhibition of dengue viruses by N-methylcytisine thio derivatives through targeting viral envelope protein and NS2B-NS3 protease

  • Bioorg Med Chem Lett. 2024 Jan 18:99:129623. doi: 10.1016/j.bmcl.2024.129623.
Chen-Sheng Lin 1,  Chih-Hao Lu 2,  Tsai-Hsiu Lin 3,  Yan-Tung Kiu 4,  Ju-Ying Kan 5,  Yu-Jen Chang 6,  Ping-Yi Hung 4,  Alena V Koval'skaya 7,  Dmitry O Tsypyshev 7,  Inna P Tsypysheva 8,  Cheng-Wen Lin 9
Affiliations

Affiliations

  • 1 Division of Gastroenterology, Kuang Tien General Hospital, No. 117, Shatian Rd, Shalu District, Taichung City 433, Taiwan.
  • 2 Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu City, Taiwan.
  • 3 Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan; Department of Laboratory Medicine, China Medical University Hospital, Taichung 40402, Taiwan.
  • 4 Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan.
  • 5 Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan; The Ph.D. Program of Biotechnology and Biomedical Industry, China Medical University, Taichung, Taiwan.
  • 6 The Ph.D. Program of Biotechnology and Biomedical Industry, China Medical University, Taichung, Taiwan.
  • 7 Ufa Institute of Chemistry, Ufa Federal Research Centre of the Russian Academy of Sciences, 71 prosp. Oktyabrya, 450054 Ufa, Russian Federation.
  • 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 40402, Taiwan; The Ph.D. Program of Biotechnology and Biomedical Industry, China Medical University, Taichung, Taiwan; Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung41354, Taiwan. Electronic address: cwlin@mail.cmu.edu.tw.
PMID: 38242331 DOI: 10.1016/j.bmcl.2024.129623
Abstract

Dengue virus (DENV) is a significant global health threat, causing millions of cases worldwide each year. Developing Antiviral drugs for DENV has been a challenging endeavor. Our previous study identified anti-DENV properties of two (-)-cytisine derivatives contained substitutions within the 2-pyridone core from a pool of 19 (-)-cytisine derivatives. This study aimed to expand on the previous research by investigating the Antiviral potential of N-methylcytisine thio (mCy thio) derivatives against DENV, understanding the molecular mechanisms of Antiviral activity for the active thio derivatives. The inhibitory assays on DENV-2-induced cytopathic effect and infectivity revealed that mCy thio derivatives 3 ((1R,5S)-3-methyl-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocine-8-thione) and 6 ((1S,5R)-3-methyl-2-thioxo-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one) were identified as the active compounds against both DENV-1 and DENV-2. Derivative 6 displayed robust Antiviral activity against DENV-2, with EC50 values ranging from 0.002 to 0.005 μM in different cell lines. Derivative 3 also exhibited significant Antiviral activity against DENV-2. The study found that these compounds are effective at inhibiting DENV-2 at both the entry stage (including virus attachment) and post-entry stages of the viral life cycle. The study also investigated the inhibition of the DENV-2 NS2B-NS3 Protease activity by these compounds. Derivative 6 demonstrated notably stronger inhibition compared to mCy thio 3, revealing its dual Antiviral action at both the entry and post-entry stages. Molecular docking simulations indicated that mCy thio derivatives 3 and 6 bind to the domain I and III of the DENV E protein, as well as the active of NS2B-NS3 Protease, suggesting their molecular interactions with the virus. The study demonstrates the Antiviral efficacy of N-methylcytisine thio derivatives against DENV. It provides valuable insights into the potential interactions between these compounds and viral target proteins, which could be useful in the development of Antiviral drugs for DENV.

Keywords

Antiviral; Attachment; Dengue virus; E protein; Entry; N-methylcytisine thio derivative; NS2B-NS3 protease; Post-entry.

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