William Haseltine
William Haseltine

It is becoming increasingly clear that we have misunderstood SARS-CoV-2, the virus that causes COVID-19. Many people, including some experts in the scientific community, deemed the pandemic over with the release of the mRNA vaccines. The belief—or perhaps it was hope in disguise—was that with the development of the vaccines, we could go back to living our lives as usual, back to a semblance of pre-pandemic normalcy. This simply is not so, as evidenced by surging cases around the world and the continued onslaught of variant after variant.

Even the latest approach, trying to play catch-up with variants by updating our vaccines to match the dominant circulating strain, is a losing game; we will always be one step behind, forced to adapt to the cards we are dealt rather than dictating the playing field. This should come as no surprise. Across the globe, highly skilled influenza researchers have been battling for decades to develop long-lasting, broadly neutralizing flu shots. Although plenty of progress has been made, we still have yearly flu seasons, some of which are plagued by low vaccine efficacy—in 2021/2022, the vaccine was only 36% effective at preventing influenza cases requiring medical attention.1

At this point, we seem to have accepted that we will be living with COVID-19 for the foreseeable future; such complacency is very dangerous. “Living with the virus” is no different from living with a pet lion; there is never any guarantee of safety. We know SARS-CoV-2 can change rapidly, we know it can become far more virulent, and we have no idea of the determinants of pathogenesis.

Our single-minded reliance on vaccines, at the expense of developing novel drug therapies, has left us fighting with one hand tied behind our back. Our current antivirals are anemic at best: they are either no longer effective, like most monoclonal antibodies, or they simply cannot prevent infection in the first place. If we ever hope to control COVID-19, we need to join the battle fully. This means a dramatic increase in resources to fund drug development efforts. The problem is not a lack of tools; it is a lack of political, scientific, and economic will. It is time to change that.

What follows is a summary of the shortcomings of our currently available antiviral drugs as well as a brief overview of some promising, up-and-coming contenders.

Revisiting Available COVID-19 Drugs and Treatments: Not Good Enough

1. Monoclonal Antibodies (mAbs)

Monoclonal antibodies are antibodies designed to target a specific antigen or even a specific region of an antigen, usually the spike protein. Once the antibodies bind to the antigen, they either block it from being able to bind to our cells or mark it for destruction by other immune cells. As such, they work well in instances where they correctly match up to the antigen at hand—successfully neutralizing the virus and inhibiting infection—but suffer from the same major issues as vaccines: viral resistance and viral mutation.2 With repeat or extended exposure to a certain antibody, SARS-CoV-2 will eventually mutate to escape the immune system, rendering the antibody ineffective and even in the absence of resistance, run-of-the-mill viral mutation can have the same effect.

Monoclonal antibodies come with the additional drawback of needing to be administered intravenously or subcutaneously by a healthcare professional. None of the currently available options come in an oral format, as a pill. This means people with mild-to-moderate disease—not bad enough to warrant hospitalization—often do not receive treatment and, while sick, run the risk of infecting others. Practically speaking, monoclonal antibodies simply cannot be used prophylactically; they may help you once you’re in the hospital, but they won’t be able to stop you from ending up there in the first place.

2. Paxlovid

Paxlovid is a kinase inhibitor that interferes with the main protease (Mpro) of SARS-CoV-2; it is highly efficacious, safe, and is taken orally. Early clinical trial results confirmed its promise, indicating a near-90% reduction in the risk of COVID-19–related hospitalizations and deaths.3 Even in a highly vaccinated population, the drug was able to reduce hospitalization or death by 44% in adults over 50 years of age.4 And unlike monoclonal antibodies, viral resistance and viral variation pose less of an issue for Paxlovid because the main protease is a highly conserved region of the SARS-CoV-2 genome. Whereas the spike protein can undergo large structural changes without too heavy of a sacrifice on viral fitness, this is simply not true of the main protease.5

So what are the drawbacks? First on the list is a phenomenon that has been termed “Paxlovid rebound.” This occurs when, following a full course of the medication and apparent clearance of the virus, symptoms suddenly return. Although this may happen even in the absence of antiviral treatments—one preprint indicates that up to 10% of infections are followed by a rebound in symptoms and 12% by a rebound in viral levels— it is more common in those treated with Paxlovid.6,7 The main limitation facing Paxlovid, however, is its inability to prevent infection.8 As such, it cannot be used in a pre- or post-exposure context, cannot avert onward transmission, and cannot contain the pandemic. It is a great start and points us in the right direction, but it is not the final solution.

3. Remdesivir

Remdesivir is a nucleoside analogue that works by inhibiting RNA-dependent RNA polymerase—the enzyme that builds up viral RNA chains during replication. Despite being a nucleotide analogue, it does not carry the mutagenic risk of molnupiravir; rather than being incorporated into the viral genome and then introducing errors, it works by being incorporated into the viral genome and then stalling the inclusion of any additional nucleosides.

Still, remdesivir suffers from other issues. First and foremost is the problem of low efficacy. Results from the World Health Organization (WHO) Solidarity Trial, a randomized trial that enlisted roughly 3,000 people, concluded that remdesivir has no significant effect on patients with COVID-19 who are already being ventilated.9 For hospitalized patients not requiring ventilation, remdesivir had only a small, nonsignificant effect on death or progression to ventilation.

Another major drawback of remdesivir is the fact it must be administered intravenously across the span of multiple days. As with monoclonal antibodies, this significantly limits its practicality for everyday use. It also means that it cannot be used in a prophylactic capacity.

4. Molnupiravir

Molnupiravir works by inserting errors into the viral genome.10 These errors are then copied during replication, and when enough of them accrue, viral proteins end up with too many mutations to properly function, incapacitating the virus. The main issue facing molnupiravir is low efficacy. It was initially touted to reduce the risk of hospitalization and death by up to 50%, but this number dropped down to 30% by the end of the full clinical trial.11,12 Since then, new data from the largest randomized trial of molnupiravir, which enlisted a total of 26,000 individuals, indicate that molnupiravir offers no reduction in the frequency of COVID-19–associated hospitalizations or deaths in high-risk vaccinated adults.13 Whether you take molnupiravir or you take a placebo, your odds are the same.

The low efficacy is further problematized by a dubious safety profile. Owing to a shared intermediate required in both the synthesis of viral RNA as well as human DNA—ribonucleoside 5′-diphosphate—molnupiravir may pose a mutagenic threat to humans: instead of introducing errors only to viral RNA, the drug may also lead to host DNA mutations.14 Long term, this could result in the growth of cancerous tumors and even birth defects, either through mutated sperm precursor cells or if given directly to pregnant women.

Molnupiravir’s mechanism of action also carries the risk of spawning new viral variants. Recall that its entire modus operandi is, essentially, destruction via mutation. Certain scenarios, some as banal as a person forgetting to finish their full course of medication, may bring about all of the mutation with none of the destruction. The risk of such viral mutations following treatment with molnupiravir is especially acute in immunocompromised patients, where new variants can form as quickly as a day or two.15

Up-and-Coming COVID-19 Therapeutics: Where Are We Headed?

New Drugs, Familiar Mechanisms

Many of the novel COVID-19 drugs making their way through the development and trial pipeline are based on the same broad strategies as the antivirals discussed above. They take advantage of the same viral “weaknesses” but try to improve on the limitations of their predecessors.

Take, for example, the kinase inhibitor Xocova. Developed by Japanese pharmaceutical company Shionogi, it works in the same way as Paxlovid, by inhibiting the main protease (Mpro) of SARS-CoV-2. Early efficacy data, albeit based on a very small sample size, indicates robust antiviral activity, with a rapid decrease in viral RNA titers compared with placebo.16 That said, time until relief of symptoms was similar between the two groups.

Another group of Japanese researchers developed and tested main protease inhibitors that include fluorine atoms to increase cell membrane permeability and binding affinity for the pocket of Mpro. The team also replaced the digestible amide bond with a surrogate structure to improve biostability. The modified compounds outperformed nirmatrelvir in mouse models.17

Then there is VV116, an oral remdesivir derivative.18 Like its parent compound, it works by inhibiting the RNA-dependent RNA polymerase. Unlike its parent compound, however, VV116 matches Paxlovid in efficacy, enabling clinical recovery from mild-to-moderate COVID-19 in the same amount of time.19 And crucially, where remdesivir must be delivered via injection or intravenous drip, VV116 can be taken orally, expanding its potential reach.

Despite small improvements, such up-and-coming antivirals represent a mostly lateral move. True, they expand our arsenal of treatments against COVID-19 and help decrease the risk of viral resistance, but ultimately they differ from our current antivirals in degree, not in kind. Like Paxlovid, molnupiravir, monoclonal antibodies, and remdesivir, none of them will work prophylactically—they can only treat, not prevent.

Exploiting Vulnerabilities: Strategies for Prophylactic Drug Design

With an eye toward prevention, it’s clear we need to diversify our lines of attack against SARS-CoV-2. What follows is a broad overview of strategies that may yield more success in the pursuit of prophylactic antivirals.

COVID-19 begins when SARS-CoV-2 first encounters cells in the upper airway that express a suitable attachment site, the angiotensin converting enzyme 2 (ACE 2). But entry into the target cells requires much more than surface attachment; after the virus has attached itself to ACE2, it still needs to fuse with the host cell membrane in order to inject its genetic material into the cytoplasm, where replication can begin. To fuse with the host membrane, SARS-CoV-2 depends on certain human enzymes—furin, transmembrane serine proteases (TMPRSSs), and cathepsins (CTSs)—to cleave its spike (S) protein. Inhibition of ACE2-binding or of membrane fusion blocks viral entry, short circuiting infection before it ever gets a foothold.

investigation and research dna, virus, bacteria
Credit: CMB / Getty Images

Binding and fusion are complex processes with many moving parts, rendering them sites of potential failure. Scientists have begun exposing these vulnerabilities and leveraging them to their advantage.

1. Potential therapies targeting the human ACE2 receptor of the viral spike protein

A massive survey of 2,900 FDA-approved drugs revealed that carvedilol, a beta blocker used to treat high blood pressure and heart failure, may also prove useful against SARS-CoV-2.20 To test its suitability, researchers exposed human lung cells (A549-ACE2) to carvedilol for two hours before infecting them with SARS-CoV-2. After two days of incubation, they checked the cells for the presence of SARS-CoV-2 spike protein, used as a marker of infection. At a half-maximal effective concentration of 4.1 µM, carvedilol successfully cleared infection. Further, assessment of two large COVID-19 databases indicated that carvedilol-use was associated with a 17% lower risk of a COVID-19 positive test result. Although the exact mechanism of action through which carvedilol inhibits SARS-CoV-2 entry into cells is unknown, the researchers suggest this may happen through disruption of spike protein–ACE2 interactions.

Another candidate, aloperine, comes by way of a medicinal plant called Sophora alopecuroides L. Isolated from the seeds of the plant, aloperine and its various derivatives have previously been shown to impair viral entry of HIV-1 and influenza.21 A recent study indicates that aloperine’s antiviral activity extends to SARS-CoV-2, successfully inhibiting entry into host cells in vitro.22 Compound 5, one of many aloperine-derivatives, proved especially effective, capable of limiting viral entry not only against pseudotyped viruses with the D614G variant of the spike protein, but also against Delta and Omicron variants. Confocal microscopy suggests that compound 5 inhibits viral entry before fusion to the cell or endosomal membrane.

Then there are a variety of ACE2 “decoys,” which mimic the receptor protein and trick the virus into binding to them instead of binding the real thing.23 Once the SARS-CoV-2 spike protein binds to the decoy, it undergoes irreversible structural changes that prevent it from being able to bind to ACE2 down the line, effectively blocking viral entry. ACE2 decoys come with the added benefit of being broadly-neutralizing; whereas SARS-CoV-2 evolves to escape monoclonal antibodies, evolution selects for ACE2 affinity. Thus, viral resistance to ACE2 decoys would come at the expense of its ability to bind ACE2, impairing infectivity and overall viral fitness. ACE2 decoys remain effective against the Omicron family of SARS-CoV-2.

2. Therapies targeting viral membrane fusion

In addition to fusing with the cell membrane directly, SARS-CoV-2 can inject its genetic material into cells by being absorbed into the cell in a vesicle, a process known as endocytosis, and then fusing with the membrane of the endosome once inside the cell. Obatoclax, an experimental drug for the treatment of cancers, was found to deliver a “double strike” against SARS-CoV-2, blocking both direct membrane fusion as well as endocytosis; it blocks direct membrane fusion by reducing furin activity and it blocks endocytosis by reducing the activity of cathepsin L.24 In vitro, obatoclax retained its potency against the spike proteins of different variants, including Alpha, Beta, and Delta. The study was performed prior to the emergence of Omicron.

An additional approach to blocking cathepsin L–mediated entry of SARS-CoV-2 involves the use of the RNA-editing tool Genome-wide Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas13. With the help of CRISPR-Cas13, researchers knocked down cathepsin L messenger RNA (mRNA) in the lungs of mice, significantly reducing viral entry.25 To deliver the CRISPR-Cas13 specifically to the lungs—leaving cathepsin L untouched in the spleen and the liver—they engineered lung-selective lipid nanoparticles (LNPs). Both prophylactic and therapeutic administration of the lung-specific CRISPR-Cas13d–based therapy effectively inhibits lethal SARS-CoV-2 infection in mice. Significantly, this approach inhibited infection not only against wild-type SARS-CoV-2 and against the Delta variant, but also against SARS-CoV-1, the cause of the 2003 SARS outbreak.

Cathepsin L is one of the two main proteases that SARS-CoV-2 depends on for viral entry into host cells. The other, as mentioned above, is TMPRSS2. A group of German scientists tested nafamostat mesylate, a kinase inhibitor that targets TMPRSS2 and is approved for treatment of pancreatitis in Japan, for its ability to block SARS-CoV-2 infection. Indeed, the compound strongly suppressed viral entry in vitro.26 A separate study, using kinase inhibitors to simultaneously block TMPRSS2 and cathepsin B, yielded similar results, with a reduction of viral load to 0.036% in ACE2-expressing human induced pluripotent stem cells.27 These results held up against multiple variants.


As much as we would like to pretend otherwise, the COVID-19 pandemic does not end where vaccines begin. At least not the current vaccines. XBB.1.5 is just the latest reminder that, as long as SARS-CoV-2 continues to spread and mutate we will continue to see waves of infection.

This is not to say that vaccines do not have their place in the fight against COVID-19, they clearly do, but rather that they are not the panacea that many hoped and that some claimed they would be. Vaccination is one protective strategy, but we cannot put all of our eggs in a single basket. And if we do, we should not be surprised when they end up cracking. Vaccines protect against the worst of COVID-19, but they do so only for a limited duration and against a limited number of variants. This won’t change anytime soon.

What can we do to help improve our odds against SARS-CoV-2? We need to actively expand our arsenal of anti-COVID-19 drugs. In particular, it should have dawned on us that we need to develop combinatorial drug therapies that can be used prophylactically, to prevent infection and stop onward transmission. We still do not have a vaccine for human immunodeficiency virus (HIV), for example, but new infections and deaths continue to decline.28 We owe this largely to antiretroviral therapy (ART) and pre-exposure prophylactic (PrEP) medication. Antiretrovirals help those who are HIV positive suppress viral loads to undetectable levels. Undetectable = untransmittable, meaning they cannot pass the virus on to others.29 Similarly, pre-exposure prophylactic (PrEP) medication helps protect those at high-risk of exposure to HIV. As long as it is taken as prescribed, it prevents the virus from taking hold in the body.

If we hope to ever contain SARS-CoV-2, we need to pursue a similar strategy. My recommendation is the following: in the United States, a “warp-speed”-like project between government, industry, and academia and a minimum of five billion, or up to ten billion, additional dollars per year to fund such collaborations.30 A similar commitment to public health and drug development must be echoed by others, especially the European Union and China. We also need to make sure we have global clinical trial capabilities in place, so that wherever outbreaks occur, we are prepared to test novel drugs on the spot. It is time to fight the battle with both hands, not just one.



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William R. Haseltine, PhD, is chair and president of the think tank ACCESS Health
International, a former Harvard Medical School and School of Public Health professor and founder of the university’s cancer and HIV/AIDS research departments. He is also the founder of more than a dozen biotechnology companies, including Human Genome Sciences.

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