More is always better than one: The n‐terminal domain of the spike protein as another emerging target for hampering the sars‐cov‐2 attachment to host cells

Abstract

Although the approved vaccines are proving to be of utmost importance in containing the Coronavirus disease 2019 (COVID‐19) threat, they will hardly be resolutive as new severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2, a single‐stranded RNA virus) variants might be insensitive to the immune response they induce. In this scenario, developing an effective therapy is still a dire need. Different targets for therapeutic antibodies and diagnostics have been identified, among which the SARS‐CoV‐2 spike (S) glycoprotein, particularly its receptor‐binding domain, has been defined as crucial. In this context, we aim to focus attention also on the role played by the S N‐terminal domain (S1‐NTD) in the virus attachment, already recognized as a valuable target for neutralizing antibodies, in particular, building on a cavity mapping indicating the presence of two druggable pockets and on the recent literature hypothesizing the presence of a ganglioside‐binding domain. In this perspective, we aim at proposing S1‐NTD as a putative target for designing small molecules hopefully able to hamper the SARS‐CoV‐2 attachment to host cells.