As the virus evolves, so too must we: a drug developer's perspective : We need a new paradigm in searching for next-generation countermeasures.

The SARS-CoV-2 virus has been raging globally for over 2 years with no end in sight. It has become clear that this virus possesses enormous genetic plasticity, and it will not be eradicated. Under increasing selective pressure from population immunity, the evolution of SARS-CoV-2 has driven it towards greater infectivity, and evasion of humoral and cellular immunity. Omicron and its expanding army of subvariants and recombinants have impaired vaccine protection and made most antibody drugs obsolete. Antiviral drugs, though presently effective, may select for more resistant strains over time. It may be inevitable, then, that future SARS-CoV-2 variants will be immune to our current virus-directed countermeasures. Thus, to gain control over the virus, we need to adopt a new paradigm in searching for next-generation countermeasures and develop host-directed therapeutics (HDTx) and host-directed antivirals (HDA). Different from the virus-directed countermeasures, HDTx and HDA may offer variant agnostic treatment to reduce the risk and severity of infections. In addition, they may exert more uniform effects against the genetically diverse SARS-CoV-2 quasispecies, thereby diminishing the risk of selecting resistant variants. Some promising HDTx and HDA approaches are summarized here.

Sec61 Inhibitor Apratoxin S4 Potently Inhibits SARS-CoV-2 and Exhibits Broad-Spectrum Antiviral Activity.

There is a pressing need for host-directed therapeutics that elicit broad-spectrum antiviral activities to potentially address current and future viral pandemics. Apratoxin S4 (Apra S4) is a potent Sec61 inhibitor that prevents cotranslational translocation of secretory proteins into the endoplasmic reticulum (ER), leading to anticancer and antiangiogenic activity both in vitro and in vivo. Since Sec61 has been shown to be an essential host factor for viral proteostasis, we tested Apra S4 in cellular models of viral infection, including SARS-CoV-2, influenza A virus, and flaviviruses (Zika, West Nile, and Dengue virus). Apra S4 inhibited viral replication in a concentration-dependent manner and had high potency particularly against SARS-CoV-2 and influenza A virus, with subnanomolar activity in human cells. Characterization studies focused on SARS-CoV-2 revealed that Apra S4 impacted a post-entry stage of the viral life-cycle. Transmission electron microscopy revealed that Apra S4 blocked formation of stacked double-membrane vesicles, the sites of viral replication. Apra S4 reduced dsRNA formation and prevented viral protein production and trafficking of secretory proteins, especially the spike protein. Given the potent and broad-spectrum activity of Apra S4, further preclinical evaluation of Apra S4 and other Sec61 inhibitors as antivirals is warranted.