Coronavirus 19 disease, caused by the new coronavirus β SARS-CoV-2, has created a global pandemic never seen in a century. Rapid global efforts have allowed the characterization of the virus and its pathogenic mechanism. An early key finding is that SARS-CoV-2 uses spike proteins, the virus’s most exposed structures, to bind to human ACE2 receptors and initiate cell invasion.
The competitive target of the spike protein is a promising strategy to neutralize virus infectivity. This review article summarizes the discovery, binding modes, and eventual applications of various classes of (bio) molecules that target the peak protein: antibodies, nanobodies, soluble ACE2 variants, mini protein, peptides, and small molecules.
The new β-coronavirus SARS-CoV-2 (SARS = severe acute respiratory syndrome) emerged in late 2019 from a zoonotic source and has since caused a global pandemic.1,2 SARS-CoV-2 infection can lead to coronavirus-19 disease (COVID-19) with symptoms ranging from mild illness to severe lung injury and multi-organ failure, eventually leading to death, especially in older patients with other comorbidities.3 With 50 million confirmed cases and more than 1.2 million deaths (as of November 2020), SARS-CoV-2 has spread more than the closely related SARS-CoV-1 and MERS-CoV.4,5
Coronaviruses display multiple copies of the spiky glycoprotein on their surface (Fig. 1A) .6 The characteristic corona shape inspired this family of viruses to be called corona (Latin for corona). The Spike proteins7,8 are, therefore, the most exposed structures of the virus.9 The Spike protein is a trimeric fusion protein consisting of the S1 and S2 subunits (Fig. 1C). The S1 unit contains the receptor-binding domain (RBD) responsible for host cell recognition and engagement.
The RBD can assume an ‘up’ or ‘down’ conformation. 10 As previously shown for SARS-Cov-1, the RBD of SARS-CoV-2 binds with high affinity (Kd ∼ 10 nM) to the angiotensin-converting enzyme 2 (ACE2) receptor conformation to initiate an invasion. from eukaryotic cells.11-13 Receptor binding destabilizes the prefusion trimer and is followed by proteolytic cleavage between the S1 and S2 units (eg, by the transmembrane serine protease TMPRSS2). cell rearrangements and invasion (Fig. 1B).
Among several potential drug targets for SARS-CoV-2, 15 the crucial function of the spike protein makes it a vulnerable and important target for virus neutralization.16 Neutralization mechanisms may depend on the direct competition for the site binding of ACE2, steric hindrance of ACE2 binding of adjacent binding sites, or in inhibition of structural rearrangements necessary for fusion.