Action, not reaction

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).

Figure 1: Broad-spectrum antiviral strategies that work against a wide range of viruses have excellent potential as first-line countermeasures against not only known but also currently unknown and understudied viruses. Credit: Reproduced from Nature Materials (2020), DOI: 10.1038/s41563-020-0698-4.

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).

Figure 2: Precision-engineered peptides (green spirals) can selectively disrupt high-curvature membranes of enveloped viruses (blue-pink balls), effectively inhibiting viral entry into human cells. Credit: Engineering in Translational Science Group, NTU/Cho Nam-Joon.

 

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.

Author: Cho Nam-Joon
Prof Cho Nam-Joon of NTU’s School of Materials Science and Engineering is the Materials Research Society of Singapore Chair in Materials Science and Engineering and an affiliated principal investigator in NTU’s Singapore Centre for Environmental Life Sciences Engineering. Parts of the research presented here have been published in Nature Materials (2020), DOI: 10.1038/s41563-020-0698-4; Nature Materials (2018), DOI: 10.1038/s41563-018-0194-2; ACS Infectious Diseases (2018), DOI: 10.1021/acsinfecdis.8b00286; Small (2016), DOI: 10.1002/smll.201500854; and Gastroenterology (2015), DOI: 10.1053/j.gastro.2014.11.043.
The article appeared first in NTU’s research & innovation magazine Pushing Frontiers (issue #17, August 2020).

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