A dual inhibitor of PIP5K1C and PIKfyve prevents SARS-CoV-2 entry into cells
2024
Yuri Seo | Yejin Jang | Seon-gyeong Lee | Joon Ho Rhlee | Sukyeong Kong | Thi Tuyet Hanh Vo | Myung hun Kim | Myoung Kyu Lee | Byungil Kim | Sung You Hong | Meehyein Kim | Joo-Yong Lee | Kyungjae Myung
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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