2. Academic Validation
  3. Novel compounds with dual inhibition activity against SARS-CoV-2 critical enzymes RdRp and human TMPRSS2

Novel compounds with dual inhibition activity against SARS-CoV-2 critical enzymes RdRp and human TMPRSS2

  • Eur J Med Chem. 2024 Jul 11:276:116671. doi: 10.1016/j.ejmech.2024.116671.
Sameh S M Soliman 1,  Alshaimaa M Hamoda 2,  Yogendra Nayak 3,  Ahmed Mostafa 4,  Rania Hamdy 5
Affiliations

Affiliations

  • 1 Research Institute for Medical and Health Sciences, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates; College of Pharmacy, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates. Electronic address: ssoliman@sharjah.ac.ae.
  • 2 Research Institute for Medical and Health Sciences, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates; College of Medicine, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates; Department of Pharmacognosy, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt.
  • 3 Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India.
  • 4 Center of Scientific Excellence for Influenza Viruses, National Research Centre, Giza, 12622, Egypt; Disease Intervention & Prevention and Host Pathogen Interactions Programs, Texas Biomedical Research Institute, San Antonio, TX, 78227, United States.
  • 5 Research Institute for Medical and Health Sciences, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates; Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
PMID: 39004019 DOI: 10.1016/j.ejmech.2024.116671
Abstract

COVID-19 caused major worldwide problems. The spread of variants and limited treatment encouraged the design of novel anti-SARS-CoV-2 compounds. A series of compounds RH1-23 were designed to dually target RNA-dependent RNA polymerase (RdRp) and transmembrane serine Protease 2 (TMPRSS2). Compared to remdesivir, in vitro screening indicated the highest selectivity and potent activity of RH11-13 with half maximum inhibitory concentration (IC50) 3.9, 5.7, and 19.72 nM, respectively. RH11-12 showed superior inhibition activity against TMPRSS2 and RdRP with IC50 (1.7 and 4.2), and (6.1 and 4.42) nM, respectively. WaterMap analysis and molecular dynamics studies demonstrated the superior Enzyme binding activity of RH11 and RH12. On Vero-E6 cells, RH11 and RH12 significantly inhibited the viral replication with 66 % and 63.2 %, and viral adsorption with 44 % and 65 %, alongside virucidal effect with 51.40 % and 90.5 %, respectively. Furthermore, the potent activity of RH12 was tested on TMPRSS2-expressing cells (Calu-3) compared to camostat. RH12 exhibited selectivity index (26.05) similar to camostat (28.01) and comparable to its SI on Vero-E6 cells (22.6). RH12 demonstrated also a significant inhibition of the viral adsorption on Calu-3 cells with 60 % inhibition at 30 nM. The designed compounds exhibited good physiochemical properties. These findings indicate a broad-spectrum Antiviral efficacy of the designed compounds, particularly RH12, with a promise for further development.

Keywords

COVID-19; Dual inhibition activity; RdRp; SARS-CoV-2; TMPRSS2; WaterMap analysis.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-162719
    SARS-CoV-2抑制剂
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