COVID19 therapeutics: Expanding the antiviral arsenal

Worldwide vaccination will greatly reduce SARS-CoV-2 transmission and severe COVID19. Yet even after mass vaccination, the virus may not be extinguished infected animal reservoirs will remain and there may be intrusions of the virus back into humans, possibly as variant forms that can circumvent immunizing antiviral antibodies [1]. Inspiring advances in vaccinology and antiviral drug development are taking place to face the challenges of animal virus spillover and possible resurgence of virulence in humans. Adaptable vaccine platforms are in place to protect against variants of concern, and therapeutic regimens are developing to limit early stages of virus growth as well as later life-threatening immunopathological sequelae of infection. The scope of the problem, however, calls for a larger arsenal of vaccines and antiviral agents. Hoffmann et al. [[2]; in this issue] are amongst those answering the call. Their works build from decades of research on the mechanisms by which CoVs enter into host cells. CoV-cell entry is a multistep process in which viral spike proteins first attach to cell receptors and then become “activated” into forms that can catalyze the final essential step in which virus and cell membranes fuse together. Activation requires fusion-catalyzing spike protein fragments that are generated through proteolysis. Host-cell proteases execute the activating proteolytic cleavages, and therefore, inhibitors disabling these host proteases are effective antiviral agents [3]. Yet there are complicating factors in developing protease inhibitors as anti-CoV drugs. During cell entry, CoVs can traverse several cell-surface and endosomal regions before fusing into host membranes, and at each place on the entry pathway there may be several different proteases that can mediate the necessary “activating” scission of spike proteins [4]. Indeed, findings made prior to the COVID19 pandemic made it clear that different members of a relatively large type II transmembrane serine protease (TTSP) family can cleave and activate CoV spikes [5]. Hence the questions: How many different TTSP family members might activate SARS-CoV-2 for virus-cell fusion, and if several can, will a single protease inhibitor block them all and thereby have potential clinical antiviral utility?