2. Academic Validation
  3. A dual inhibitor of PIP5K1C and PIKfyve prevents SARS-CoV-2 entry into cells

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

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. mkim@krict.re.kr.
  • 9 Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, Republic of Korea. mkim@krict.re.kr.
  • 10 Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Republic of Korea. leejooyong@cnu.ac.kr.
  • 11 Center for Genomic Integrity, Institute for Basic Science (IBS), Ulsan, Republic of Korea. kmyung@ibs.re.kr.
  • 12 Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea. kmyung@ibs.re.kr.
  • # 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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