dependent on the interaction of at least nine different viral proteins, and these interfaces present additional targets. Other targets are constrained secondary RNA structures in the 5′ untranslated region, the frame-shift motif of the SARS-CoV-2 genome, the host protease TMPRSS2 utilized for viral entry, dihydroorotate dehydrogenase, and SIRT2 (35).An interesting potential antiviral agent is a soluble recombinant form of the ACE2 receptor that prevents binding of the viral spike protein to cell-bound ACE2, reducing SARS-CoV-2 load in vivo (36) and potentially overcoming spike protein variant escape. Remdesivir and recombinant soluble ACE2 target different modalities of the SARS-CoV-2 life cycle, and in vitro the combination lengthened therapeutic windows against SARS-CoV-2 (37).Challenges exist in prioritizing candidates for development. Drugs are often selected on the basis of activity in cell culture systems (sarscov2.assaytracker.net) with limited consistency, often due to the different cell types used for screening. Small-animal disease models poorly mirror some aspects of human disease, such as extrapulmonary manifestations. Human testing is vital but establishing early clinical proof-of-concept is challenging, partially due to a lack of defined standardized antiviral clinical trial endpoints.The ideal antiviral agent in the current pandemic would be potently active against both current and future variants, with a good safety profile. One approach against variants, which would also assist in future pandemics, is to develop drugs with broad potential against viral families with pandemic potential: not only other coronaviruses, but also orthomyxoviruses, henipaviruses, filoviruses, and others. One option is HTAs that inhibit human host cell proteins responsible for viral replication and spread. The host is constant and less likely to drive escape variants, making HTAs truly broad-spectrum.Historically, investment in HTA development has been poor, resulting in few options in use. However, the potential of broad-spectrum antivirals has recently been recognized by the National Institute of Allergy and Infectious Diseases and the Coalition for Epidemic Preparedness Innovation, but finding agents to directly act against common targets has proven elusive as viruses within and across families are extremely divergent. Developing HTAs takes time, as does DAA development. However, HTA-development does not require detailed structural knowledge of viral proteins and agents could therefore be developed in between outbreaks and used at the outset of the next pandemic. Safety concerns are often raised with HTAs, given they inhibit host targets; however, nearly all our therapeutics target the host, and all therapies, even DAAs, have the potential for toxicity, so this should not deter us from developing HTAs.One promising target for HTAs is protein glycosylation, in particular enzymes involved in glycan-mediated endoplasmic reticulum quality control (ERQC) of viral glycoprotein folding (38). Iminosugars, which interfere with ERQC enzymes and have activity against SARS-CoV-2 (39), are orally available small-molecule drugs that are cheap to produce. Miglustat, an off-patent approved repurposable iminosugar, showed antiviral effects against SARS-CoV-2 in various cellular screens (39) and is due for testing in the proposed PLAT-COV platform trial. MON-DNJ, another iminosugar with phase 1 trial data, is active against SARS-CoV-2 in a cellular screen using human lung epithelial cells and reduces mortality in mice infected with influenza and dengue virus (40). Strategies against future viral threats might utilize such cost-effective orally available broad-spectrum antivirals. Soon after emergence of the virus, they might be deployed to reduce epidemic potential, and once virus-specific DAAs are developed, they could be included in more effective combination therapies that might also delay the emergence of variants of concern. Developing a suite of HTAs is a high priority for this pandemic and as insurance for the future.SARS-CoV-2–Targeting Neutralizing mAbs.SARS-CoV-2 mAbs bind to the receptor binding domain of the SARS-CoV-2 spike glycoprotein, preventing viral entry into host cells. The fine specificity of mAbs limits their potential “off-target” toxicity but also makes them vulnerable to emergence of viral variants. In patients with mild-to-moderate COVID-19, bamlanivimab-etesevimab significantly reduced the composite outcome of hospitalization, emergency department visit, or death (7.2% vs. 2.3%) (41). The emergency use authorization for using bamlanivimab alone was revoked less than 6 mo after approval due to the increasing prevalence of viral variants, resulting in an increased risk of treatment failure (42, 43). Sotrovimab, derived from a survivor of SARS-CoV-2 infection, targets a conserved epitope in the receptor binding domain away from the ACE2 binding site and may therefore maintain effectiveness with viral variants (44), but this is not guaranteed. Recently, mAbs were found to have increased efficacy in patients who were seronegative for SARS-CoV-2 antibodies (43, 45, 46). Some data have suggested that the use of mAbs in hospitalized patients with COVID-19 pneumonia and decreased oxygen saturation is associated with worse outcomes in patients with existing antibodies to SARS-CoV-2 (47). More recently in RECOVERY, hospitalized SARS-