Potential role of PIM1 inhibition in the treatment of SARS-CoV-2 infection

Magda M F Ismail; Rehab R El-Awady; Amal M Farrag; Sara H Mahmoud; Noura M Abo Shama; Ahmed Mostafa; Mohamed A Ali; Mohammed H Rashed; Iman H Ibrahim

doi:10.1186/s43141-023-00520-x

Potential role of PIM1 inhibition in the treatment of SARS-CoV-2 infection

J Genet Eng Biotechnol. 2023 May 22;21(1):65. doi: 10.1186/s43141-023-00520-x.

Authors

Magda M F Ismail¹, Rehab R El-Awady², Amal M Farrag¹, Sara H Mahmoud³, Noura M Abo Shama³, Ahmed Mostafa³, Mohamed A Ali³, Mohammed H Rashed⁴, Iman H Ibrahim⁵

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.
² Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, 11884, Cairo, Egypt. rehab.elawady.pharmg@azhar.edu.eg.
³ Center of Scientific Excellence for Influenza Viruses, National Research Centre, Giza, Egypt.
⁴ Department of Clinical Pharmacy, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
⁵ Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, 11884, Cairo, Egypt. imanhassan.pharmg@azhar.edu.eg.

Abstract

Background: SARS-CoV-2 infection involves disturbing multiple molecular pathways related to immunity and cellular functions. PIM1 is a serine/threonine-protein kinase found to be involved in the pathogenesis of several viral infections. One PIM1 substrate, Myc, was reported to interact with TMPRSS2, which is crucial for SARS-CoV-2 cell entry. PIM1 inhibitors were reported to have antiviral activity through multiple mechanisms related to immunity and proliferation. This study aimed to evaluate the antiviral activity of 2-pyridone PIM1 inhibitor against SARS-CoV-2 and its potential role in hindering the progression of COVID-19. It also aimed to assess PIM1 inhibitor's effect on the expression of several genes of Notch signaling and Wnt pathways. In vitro study was conducted on Vero-E6 cells infected by SARS-CoV-2 "NRC-03-nhCoV" virus. Protein-protein interaction of the study genes was assessed to evaluate their relation to cell proliferation and immunity. The effect of 2-pyridone PIM1 inhibitor treatment on viral load and mRNA expression of target genes was assessed at three time points.

Results: Treatment with 2-pyridone PIM1 inhibitor showed potential antiviral activity against SARS-CoV-2 (IC₅₀ of 37.255 µg/ml), significantly lowering the viral load. Functional enrichments of the studied genes include negative regulation of growth rate, several biological processes involved in cell proliferation, and Interleukin-4 production, with interleukin-6 as a predicted functional partner. These results suggest an interplay between study genes with relation to cell proliferation and immunity. Following in vitro SARS-CoV-2 infection, Notch pathway genes, CTNNB1, SUMO1, and TDG, were found to be overexpressed compared to uninfected cells. Treatment with 2-pyridone PIM1 inhibitor significantly lowers the expression levels of study genes, restoring Notch1 and BCL9 to the control level while decreasing Notch2 and CTNNB1 below control levels.

Conclusion: 2-pyridone PIM1 inhibitor could hinder cellular entry of SARS-CoV-2 and modulate several pathways implicated in immunity, suggesting a potential benefit in the development of anti-SARS-CoV-2 therapeutic approach.

Keywords: NRC-03-nhCoV; Notch pathway; PIM1; PIM1 inhibitor; SARS-CoV-2.

Grants and funding

HHSN272201400006C/AI/NIAID NIH HHS/United States