Antivirals against SARS-CoV-2 by autumn?

The challenge

Viruses encode few proteins. They instead rely on host enzymes for replication and thus offer few viable drug targets. None of the currently available oral antiviral drugs are licensed for coronaviruses, and investigation into their use against SARS-CoV-2 in clinical trials has not been encouraging.4 Despite this, close to a hundred licensed antivirals are available for other pathogens and collectively save millions of lives every year.5 Most are highly specific for their target virus, and activity against different viruses is the exception rather than the rule.4 The European Union has shortlisted some intravenous medications for development, but these would not fit the UK government’s brief of oral drugs to be taken at home.6

Of the available oral compounds with broad spectrum antiviral activity, only ribavirin is licensed to treat multiple virus strains, and this is usually in combination with other drugs.5 As it has toxic effects, ribavirin is unlikely to be suitable for covid-19 prophylaxis. Favipiravir and nitazoxanide have been shown to inhibit a large number of viruses in vitro, but phase III trials have been completed only for influenza.78 Medications against other pathogens might also have anti-SARS-CoV-2 activity,8 but several repurposing attempts have ended in disappointment, including ivermectin, azithromycin, and hydroxychloroquine.4

Viruses also have very short replication times and generate large numbers of copies, resulting in mutations that can confer resistance against antiviral drugs.5 In the 1980s, trials showed that azidothymidine improved survival in people with HIV infection, and the drug was initially viewed as a success before viral resistance emerged.9 It became clear that patients required a combination of three drugs in order to avoid resistance.10 More recently, the pandemic influenza strain H1N1 has developed resistance to oseltamivir.11 If SARS-CoV-2 shares this capacity to generate escape mutations, then multiple antiviral drugs may be required in combination for effective treatment or prophylaxis.

The targets

SARS-CoV-2 does present a few potential targets for antiviral therapy. Strong evidence suggests that viral particles enter human cells using the angiotensin converting enzyme 2 receptor and a cell surface protease, TMPRSS2.8 Camostat is a TMPRSS2 inhibitor that seems safe in humans, and phase II trials are currently in progress.12 The virus may exploit enzyme components of the vesicle transport system, such as PI-3P-5-kinase (PIKfyve) to enter the host cell membrane.13 Early laboratory studies on apilimod, a PIKfyve inhibitor, look encouraging.14

Other possible targets include the virally encoded RNA dependent RNA polymerase (RdRp), which replicates the SARS-CoV-2 genome and is dissimilar to host enzymes. It seems to be highly conserved between strains, suggesting lower risk of resistant mutations.15 Favipiravir is thought to block RdRp16 and is now in phase III trials. The nucleoside analogue molnupiravir, which also targets RdRp, reduces viral transmission and disease severity in ferrets and has been well tolerated in phase I clinical trials.17

SARS-CoV-2 also produces 3CL protease, which is used for building viral particles from polypeptides. Protease inhibitors could therefore prevent virus assembly.8 Nitazoxanide may work by inhibiting both cell entry and viral particle assembly18 and seemed to improve viral clearance in patients with symptomatic covid-19 in one small trial.8 Although the government specifies oral treatments, mucosal topical medications given by nasal spray may be as effective—iota-carrageenan, a complex sugar molecule derived from seaweed, is in phase II trials after encouraging results in vitro.

Efforts to repurpose existing drugs to inhibit SARS-CoV-2 have so far been unsuccessful, and while promising new agents are under clinical development, proper evaluation of efficacy and safety will take time. Effective antivirals would be highly valuable in the fight against covid-19, yet policy must be realistic and based on evidence, not hope or unfounded optimism. The UK government’s target to deliver antiviral home treatments within the next few months seems overly ambitious, and care must be taken to ensure that the rush does not force blunders, or indeed repeat previous ones.