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