As SARS-CoV-2 spreads globally, scientists around the world are racing to develop a vaccine. However, it is estimated that it will take many months and perhaps years to develop, test, validate and deploy an anti-SARS-CoV-2 vaccine, and eventual success is not a given.
What’s more, analyses of SARS-CoV-2 infections highlight the risk that the virus is evolving, with mutations in the viral genome leading to changes in the viral structure. As such, the SARS-CoV-2 virus we target today could look different tomorrow, curtailing the impact of vaccine and drug development efforts.
Targeting today’s and tomorrow’s pandemics
While viruses can have very distinct structural features, medically important viruses often share key features that can provide the basis for broad-spectrum antiviral targeting (Figure 1).
In my lab, we aim to develop broad-spectrum antivirals that target the virus’ lipid membrane—a coating that envelopes virus particles of a wide range of virus species, including many of those implicated in recent outbreaks. An important advantage of targeting virus membranes is that antiviral drug resistance is unlikely to emerge because the viral lipid envelope is derived from host cell membranes and not encoded by the viral genome.
We have engineered bioactive peptides (small protein molecules) that are able to selectively form pores in virus membranes, leading to a rupture of the envelope and destruction of the virus. The ability of these antiviral peptides to form pores in the viral membranes is dependent on the envelope’s curvature. Specifically, the peptides are able to disrupt small, enveloped virus particles with high membrane curvature, but are unable to damage human cells that are much larger with a much lower membrane curvature (Figure 2).
In one study, we successfully treated Zika virus infection in a mouse model with engineered pore-forming antiviral peptides, demonstrating that the so-called Lipid Envelope Antiviral Disruption (LEAD) concept is effective in vivo.
Coronaviruses such as SARS-CoV-2 belong to the enveloped viruses and thus are potentially excellent targets for the LEAD strategy. As proof of concept, we tested the activity of engineered peptides against murine hepatitis virus, a species of coronavirus that infects mice, and found high antiviral activity. We are currently developing peptides with the ability to disrupt other coronavirus species, including SARS-CoV-2.
Making the host inhospitable
Another strategy to decrease the potential for the emergence of resistance as well as increase the potential for broad-spectrum activity is to use small molecule inhibitors or similar means to target host cell functions important for viral infection or replication.
Not only does targeting host proteins that are not under genetic control of the virus make it more difficult for a virus species to develop resistance through mutation, many different virus species depend on access to the same host cell function. Thus, a single drug inhibiting a key host enzyme can target multiple viral pathogens, not just those that are currently known but also related viruses that might emerge in the future.
Being prepared for the future
Being prepared to confront future viruses with broad-spectrum antiviral countermeasures—such as the LEAD concept and other mechanistic approaches—could significantly boost our ability to ward off pandemics and reshape the landscape of antiviral drug development, including what we view as “druggable” biological targets.
Most importantly, the above approaches would allow us to be proactive, instead of reactive, to emerging viral threats.