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

• Published in: Experimental & molecular medicine Vol. 56; no. 8; pp. 1736 - 1749
• Main Authors: Seo, Yuri, Jang, Yejin, Lee, Seon-Gyeong, Rhlee, Joon Ho, Kong, Sukyeong, Vo, Thi Tuyet Hanh, Kim, Myung Hun, Lee, Myoung Kyu, Kim, Byungil, Hong, Sung You, Kim, Meehyein, Lee, Joo-Yong, Myung, Kyungjae
• Format: Journal Article
• Language: English
• Published: United States Springer Nature B.V 01.08.2024; Nature Publishing Group UK; Nature Publishing Group; 생화학분자생물학회
• Subjects: ACE2; Angiotensin-converting enzyme 2; Antiviral agents; Artificial intelligence; Cathepsin L; Cathepsins; Cell activation; Cell culture; Cell membranes; COVID-19; Endocytosis; Pandemics; Proteolysis; Public health; Severe acute respiratory syndrome coronavirus 2; Spike protein; Vaccines; Viruses; 생화학
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/s12276-024-01283-2

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.