2. Academic Validation
  3. Discovery of novel papain-like protease inhibitors for potential treatment of COVID-19

Discovery of novel papain-like protease inhibitors for potential treatment of COVID-19

  • Eur J Med Chem. 2023 Jun 5;254:115380. doi: 10.1016/j.ejmech.2023.115380.
Fatema Hersi 1,  Anusha Sebastian 2,  Hamadeh Tarazi 2,  Vunnam Srinivasulu 2,  Ahmed Mostafa 3,  Abdou Kamal Allayeh 4,  Cong Zeng 5,  Ibrahim Y Hachim 1,  Shan-Lu Liu 5,  Imad A Abu-Yousef 6,  Amin F Majdalawieh 6,  Dana M Zaher 1,  Hany A Omar 7,  Taleb H Al-Tel 8
Affiliations

Affiliations

  • 1 Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; College of Medicine, University of Sharjah, Sharjah, 27272, United Arab Emirates.
  • 2 Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates.
  • 3 Center of Scientific Excellence for Influenza Viruses, Environment and Climate Change Institute, National Research Centre, Giza, 12622, Egypt.
  • 4 Virology Lab 176, Water Pollution Research Department, Environment and Climate Change Institute, National Research Centre, Dokki, Giza, 12622, Egypt.
  • 5 Center for Retrovirus Research, The Ohio State University, Columbus, OH, 43210, USA; Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, 43210, USA.
  • 6 Department of Biology, Chemistry and Environmental Sciences, College of Arts and Sciences, American University of Sharjah, P.O. Box 26666, Sharjah, United Arab Emirates.
  • 7 Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates; Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt. Electronic address: [email protected].
  • 8 Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates. Electronic address: [email protected].
PMID: 37075625 DOI: 10.1016/j.ejmech.2023.115380
Abstract

The recent emergence of different SARS-CoV-2 variants creates an urgent need to develop more effective therapeutic agents to prevent COVID-19 outbreaks. Among SARS-CoV-2 essential proteases is papain-like protease (SARS-CoV-2 Plpro), which plays multiple roles in regulating SARS-CoV-2 viral spread and innate immunity such as deubiquitinating and deISG15ylating (interferon-induced gene 15) activities. Many studies are currently focused on targeting this protease to tackle SARS-CoV-2 Infection. In this context, we performed a phenotypic screening using an in-house pilot compounds collection possessing a diverse skeleta against SARS-CoV-2 Plpro. This screen identified SIMR3030 as a potent inhibitor of SARS-CoV-2. SIMR3030 has been shown to exhibit deubiquitinating activity and inhibition of SARS-CoV-2 specific gene expression (ORF1b and Spike) in infected host cells and possessing virucidal activity. Moreover, SIMR3030 was demonstrated to inhibit the expression of inflammatory markers, including IFN-α, IL-6, and OAS1, which are reported to mediate the development of cytokine storms and aggressive immune responses. In vitro absorption, distribution, metabolism, and excretion (ADME) assessment of the drug-likeness properties of SIMR3030 demonstrated good microsomal stability in liver microsomes. Furthermore, SIMR3030 demonstrated very low potency as an inhibitor of CYP450, CYP3A4, CYP2D6 and CYP2C9 which rules out any potential drug-drug interactions. In addition, SIMR3030 showed moderate permeability in Caco2-cells. Critically, SIMR3030 has maintained a high in vivo safety profile at different concentrations. Molecular modeling studies of SIMR3030 in the active sites of SARS-CoV-2 and MERS-CoV PLpro were performed to shed LIGHT on the binding modes of this inhibitor. This study demonstrates that SIMR3030 is a potent inhibitor of SARS-CoV-2 Plpro that forms the foundation for developing new drugs to tackle the COVID-19 pandemic and may pave the way for the development of novel therapeutics for a possible future outbreak of new SARS-CoV-2 variants or other Coronavirus species.

Keywords

COVID-19; MERS-CoV; SARS-CoV-2; SARS-CoV-2 PLpro; Virucidal activity.

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