N-terminal Domain (NTD) of Spike Protein from SARS-CoV-2 May Cause COVID-19 Multiple Tropisms and Serve as a Potential Drug Target

The spike protein from coronaviruses (CoVs) can be cleaved into an N -terminal S1 subunit and a membraneembedded C-terminal S2 subunit. The S1 subunit can be further divided into two independent domains, Nterminal domain (NTD) and C-terminal domain (CTD), although sometimes a central region is defined between them. The NTD and CTD bind to co-receptors and receptors. We realize that the NTD from the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) seems not to bind to any known receptors/co-receptors. We review various CoVs according to their binding sites in the NTD and CTD. Our review shows that (1) bovine CoV (BCoV), human CoV OC43 (HCoV-OC43), avian infectious bronchitis virus (IBV) and murine hepatitis virus (MHV) use their NTD to bind to either receptors or co-receptors, (2) human CoV HKU1 (HCoV-HKU1), Middle East respiratory syndrome CoV (MERS-CoV), SARS-CoV, and porcine transmissible gastroenteritis virus (TGEV) use both NTD and CTD to bind to co-receptors and receptors, and (3) SARS-CoV-2 is the sole CoV whose NTD does not interact with any known receptors/co-receptors. Our review is helpful in understanding of SARS-CoV-2 multiple organ/tissue tropisms and in discovery and development of the therapeutic agents against SARS-CoV-2.