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
{"title":"PIP5K1C 和 PIKfyve 的双重抑制剂可阻止 SARS-CoV-2 进入细胞。","authors":"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","doi":"10.1038/s12276-024-01283-2","DOIUrl":null,"url":null,"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. The COVID-19 pandemic, triggered by the SARS-CoV-2 virus, underscores the immediate need for effective treatments, particularly for severe cases. Even with vaccines, treatments that block the virus’s entry into cells are vital. SARS-CoV-2 enters host cells by attaching to the ACE2 receptor, a process that is a prime target for intervention. This research concentrates on blocking the virus’s entry into cells as a potential treatment method. The study is an experiment using cellular models to assess the effectiveness of a new compound, UNI418, in preventing SARS-CoV-2 infection. UNI418 targets enzymes involved in cell membrane dynamics, essential for the virus’s entry. The researchers conclude that UNI418, by blocking PIP5K1C and PIKfyve, offers a promising approach to preventing SARS-CoV-2 infection and emphasizes the importance of targeting the virus’s entry process as a treatment strategy. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5000,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01283-2.pdf","citationCount":"0","resultStr":"{\"title\":\"A dual inhibitor of PIP5K1C and PIKfyve prevents SARS-CoV-2 entry into cells\",\"authors\":\"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\",\"doi\":\"10.1038/s12276-024-01283-2\",\"DOIUrl\":null,\"url\":null,\"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. The COVID-19 pandemic, triggered by the SARS-CoV-2 virus, underscores the immediate need for effective treatments, particularly for severe cases. Even with vaccines, treatments that block the virus’s entry into cells are vital. SARS-CoV-2 enters host cells by attaching to the ACE2 receptor, a process that is a prime target for intervention. This research concentrates on blocking the virus’s entry into cells as a potential treatment method. The study is an experiment using cellular models to assess the effectiveness of a new compound, UNI418, in preventing SARS-CoV-2 infection. UNI418 targets enzymes involved in cell membrane dynamics, essential for the virus’s entry. The researchers conclude that UNI418, by blocking PIP5K1C and PIKfyve, offers a promising approach to preventing SARS-CoV-2 infection and emphasizes the importance of targeting the virus’s entry process as a treatment strategy. 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A dual inhibitor of PIP5K1C and PIKfyve prevents SARS-CoV-2 entry into cells
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. The COVID-19 pandemic, triggered by the SARS-CoV-2 virus, underscores the immediate need for effective treatments, particularly for severe cases. Even with vaccines, treatments that block the virus’s entry into cells are vital. SARS-CoV-2 enters host cells by attaching to the ACE2 receptor, a process that is a prime target for intervention. This research concentrates on blocking the virus’s entry into cells as a potential treatment method. The study is an experiment using cellular models to assess the effectiveness of a new compound, UNI418, in preventing SARS-CoV-2 infection. UNI418 targets enzymes involved in cell membrane dynamics, essential for the virus’s entry. The researchers conclude that UNI418, by blocking PIP5K1C and PIKfyve, offers a promising approach to preventing SARS-CoV-2 infection and emphasizes the importance of targeting the virus’s entry process as a treatment strategy. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
期刊介绍:
Experimental & Molecular Medicine (EMM) stands as Korea's pioneering biochemistry journal, established in 1964 and rejuvenated in 1996 as an Open Access, fully peer-reviewed international journal. Dedicated to advancing translational research and showcasing recent breakthroughs in the biomedical realm, EMM invites submissions encompassing genetic, molecular, and cellular studies of human physiology and diseases. Emphasizing the correlation between experimental and translational research and enhanced clinical benefits, the journal actively encourages contributions employing specific molecular tools. Welcoming studies that bridge basic discoveries with clinical relevance, alongside articles demonstrating clear in vivo significance and novelty, Experimental & Molecular Medicine proudly serves as an open-access, online-only repository of cutting-edge medical research.