Targeting intracellular Neu1 for coronavirus infection treatment
Darong Yang,
Yin Wu,
Isaac Turan,
Joseph Keil,
Kui Li,
Michael H. Chen,
Runhua Liu,
Lizhong Wang,
Xue-Long Sun,
Guo-Yun Chen
Affiliations
Darong Yang
Children’s Foundation Research Institute at Le Bonheur Children’s Hospital, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103, USA
Yin Wu
Children’s Foundation Research Institute at Le Bonheur Children’s Hospital, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103, USA
Isaac Turan
Department of Chemistry, Chemical and Biomedical Engineering and Center for Gene Regulation of Health and Disease (GRHD), Cleveland State University, 2121 Euclid Avenue, Cleveland, OH 44115, USA
Joseph Keil
Department of Chemistry, Chemical and Biomedical Engineering and Center for Gene Regulation of Health and Disease (GRHD), Cleveland State University, 2121 Euclid Avenue, Cleveland, OH 44115, USA
Kui Li
Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38103, USA
Michael H. Chen
Children’s Foundation Research Institute at Le Bonheur Children’s Hospital, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103, USA
Runhua Liu
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35233, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA
Lizhong Wang
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35233, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA
Xue-Long Sun
Department of Chemistry, Chemical and Biomedical Engineering and Center for Gene Regulation of Health and Disease (GRHD), Cleveland State University, 2121 Euclid Avenue, Cleveland, OH 44115, USA; Corresponding author
Guo-Yun Chen
Children’s Foundation Research Institute at Le Bonheur Children’s Hospital, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103, USA; Corresponding author
Summary: There are currently no effective therapies for COVID-19 or antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and vaccines appear less effective against new SARS-CoV-2 variants; thus, there is an urgent need to understand better the virulence mechanisms of SARS-CoV-2 and the host response to develop therapeutic agents. Herein, we show that host Neu1 regulates coronavirus replication by controlling sialylation on coronavirus nucleocapsid protein. Coronavirus nucleocapsid proteins in COVID-19 patients and in coronavirus HCoV-OC43-infected cells were heavily sialylated; this sialylation controlled the RNA-binding activity and replication of coronavirus. Neu1 overexpression increased HCoV-OC43 replication, whereas Neu1 knockdown reduced HCoV-OC43 replication. Moreover, a newly developed Neu1 inhibitor, Neu5Ac2en-OAcOMe, selectively targeted intracellular sialidase, which dramatically reduced HCoV-OC43 and SARS-CoV-2 replication in vitro and rescued mice from HCoV-OC43 infection-induced death. Our findings suggest Neu1 inhibitors could be used to limit SARS-CoV-2 replication in patients with COVID-19, making Neu1 a potential therapeutic target for COVID-19 and future coronavirus pandemics.
