Viruses either fuse directly at the host plasma membrane under physiological pH or fuse at the endosome under acidic pH. SARS-CoV-2 is unusual in that the S1/S2 boundary harbors a furin cleavage site, so the spike protein is already cleaved in the mature virion. Cleavage at S1/S2 and an internal S2′ site is a pre-requisite to prime fusion in coronaviruses. The fusion mechanism, on the other hand, involving the formation of a 6-helix bundle, is conserved amongst viruses. SARS-CoV-2 and SARS-CoV-1 recognize the same receptor, the human angiotensin-converting enzyme 2 (ACE2), whereas the Middle East respiratory syndrome coronavirus (MERS-CoV) recognizes dipeptidyl peptidase 4 (DPP4). Receptor recognition is not conserved in coronaviruses.

The S1 subunits of the severe acute respiratory syndrome virus (SARS-CoV-1) and SARS-CoV-2 share 75% and 50% identity in the receptor binding domain (RBD) and the receptor binding motif, whereas the more conserved S2 subunits share 88% and 100% identity in the fusion domain and fusion peptide. The coronavirus spike protein is divided into an S1 attachment subunit and an S2 fusion subunit. In order to enter host cells to initiate an infection, the virus must recognize and bind to a host cell receptor which then triggers virus–host cell membrane fusion to release the viral nucleocapsid into the host cell cytoplasm. The post-attachment entry step is one such conserved step. Such drugs would ideally target conserved steps in the viral life cycle, be broad-spectrum, and therefore generally applicable to COVID variants of the present and future. Such first-line treatments would allow more time to develop new vaccines, could improve therapeutics, and might be employed as prophylactics in those who cannot be vaccinated or do not respond well to vaccine. We therefore lack a first line anti-viral defense to add to the current toolkit. So far, drug therapy has been limited to attempts to reduce the most life-threatening symptoms of the infection that arise due to over-stimulation of the immune response. Missing from the arsenal of effective measures to date has been an effective anti-viral therapy that could be administered prior to, or after acquiring the virus. Hence it seems appropriate to look for further control measures for the virus. Nevertheless, vaccine development and vaccination of global populations are lengthy processes. Whilst the former measures are highly unpopular, have serious impacts on economic factors, and are of limited effectiveness, vaccination has so far proven to be highly efficient. These measures range from political and societal changes aimed at limiting virus spread, to attempts at eradication, as exemplified by vaccination. The emergence of the coronavirus disease-2019 (COVID-19) has been a major global challenge that has led to unprecedented efforts to try to control the virus. We discuss the prospects of repurposing these existing drugs for treating current and future coronavirus outbreaks. The structural homology of the hits allowed the production of a well-defined pharmacophore that was found to be highly accurate in predicting the anti-viral activity of the compounds in the screen. Moreover, the compounds were able to prevent infection in both kidney- and lung-derived human cell lines. Further studies demonstrated that these “kite-shaped” molecules were surprisingly specific for SARS-CoV-1 and SARS-CoV-2 and that they acted early in the entry steps of the viral infectious cycle, but did not affect virus attachment to the cells. A group of structurally-related compounds, showing moderate inhibitory activity with IC 50 values in the 2–5 μM range, were identified. We therefore screened a small library of FDA-approved compounds for potential severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antivirals using a pseudovirus system that allows a sensitive read-out of infectivity. The long development timescales for such drugs are a major problem, but could be shortened by repurposing existing drugs. Anti-viral small molecules are currently lacking for treating coronavirus infection.

Kite shape in nature