A dual inhibitor of PIP5K1C and PIKfyve prevents SARS-CoV-2 entry into cells

  • Exp Mol Med. 2024 Aug 1. doi: 10.1038/s12276-024-01283-2.
Yuri Seo  #  1  2 ,  Yejin Jang  #  3 ,  Seon-Gyeong Lee  #  2  4  5 ,  Joon Ho Rhlee  6 ,  Sukyeong Kong  2  7 ,  Thi Tuyet Hanh Vo  1 ,  Myung Hun Kim  1 ,  Myoung Kyu Lee  3 ,  Byungil Kim  3 ,  Sung You Hong  2  6 ,  Meehyein Kim  8  9 ,  Joo-Yong Lee  10 ,  Kyungjae Myung  11  12
Affiliations
  • 1. Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Republic of Korea.
  • 2. Center for Genomic Integrity, Institute for Basic Science (IBS), Ulsan, Republic of Korea.
  • 3. Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea.
  • 4. Department of Biological Science, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
  • 5. CasCure Therapeutics, Seoul, Republic of Korea.
  • 6. Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea.
  • 7. Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
  • 8. Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea. [email protected].
  • 9. Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, Republic of Korea. [email protected].
  • 10. Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Republic of Korea. [email protected].
  • 11. Center for Genomic Integrity, Institute for Basic Science (IBS), Ulsan, Republic of Korea. [email protected].
  • 12. Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea. [email protected].
  • # Contributed equally.
PMID: 39085352 DOI: 10.1038/s12276-024-01283-2
Abstract

The SARS-CoV-2 pandemic has had an unprecedented impact on global public health and the economy. Although vaccines and antivirals have provided effective protection and treatment, the development of new small molecule-based Antiviral candidates is imperative to improve clinical outcomes against SARS-CoV-2. In this study, we identified UNI418, a dual PIKfyve and PIP5K1C inhibitor, as a new chemical agent that inhibits SARS-CoV-2 entry into host cells. UNI418 inhibited the proteolytic activation of cathepsins, which is regulated by PIKfyve, resulting in the inhibition of Cathepsin L-dependent proteolytic cleavage of the SARS-CoV-2 spike protein into its mature form, a critical step for viral endosomal escape. We also demonstrated that UNI418 prevented ACE2-mediated endocytosis of the virus via PIP5K1C inhibition. Our results identified PIKfyve and PIP5K1C as potential Antiviral targets and UNI418 as a putative therapeutic compound against SARS-CoV-2.

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