Model of the external structure of SARS-CoV-2. Orange indicates N-glycans, the target of the new broad-spectrum antivirals. Credit Alexey Solodovnikov, Valeria Arkhipova (CC BY-SA 4.0, https://creativecommons.org/licenses/by-sa/4.0/deed.en)
Promising candidates for the world’s first class of broad-spectrum antivirals have been developed in a major step forward for treating viral diseases and combating emerging pandemics.
The candidates successfully blocked a variety of enveloped viruses – Ebola, Marburg, Nipah, Hendra, MERS-CoV, SARS-CoV-1, and SARS-CoV-2 (COVID-19) – from infecting cells in the lab.
Treatment with 2 of the molecules also significantly reduced SARS-CoV-2 viral loads in the brains and lungs of infected mice with minimal toxicity.
The findings are presented in a new study in the journal Science Advances.
“Broad-spectrum antibiotics disrupt essential molecular targets that are widely conserved among bacteria, such as the cell walls, membranes, or the machinery that make nucleic acids or proteins,” write the authors of the study.
But existing antivirals are effective against only a small set of related viruses.
This is because proteins vary a lot between viral families, so an antiviral which targets a protein in one kind of virus may not recognise the same protein in another. Plus, the authors add, the high viral protein mutation rate allows the rapid development of antiviral resistance.
“This lack of treatments can leave populations vulnerable for years while vaccines and therapeutics are being developed,” says corresponding author Adam Braunschweig, a professor at the City University of New York and Hunter College in the US.
Braunschweig and his team set out to identify broad spectrum antivirals which “disrupt the action of a widely shared viral target that does not easily evolve to become resistant”.
They created 57 small molecules designed to bind to viral N-glycans – sugar molecules are found on the surfaces of enveloped viruses.
“Enveloped viruses comprise families considered to have the highest pandemic potential, case fatality, and morbidity in humans, including Coronaviridae, Filoviridae, and Paramyxoviridae,” the authors write.
“N-glycans are involved in many essential steps in the viral life cycle, including virus replication, transmission, and entry into new host cells.”
The researchers screened the ‘synthetic carbohydrate receptors’ (SCRs) for their ability to prevent live viruses from infecting cells and live mouse models.
“We further show that the mechanism of action of our SCRs involves both inhibition of viral binding to host receptors and inhibition of membrane fusion during viral entry,” the authors write.
“Our study goes further by demonstrating that this glycan-targeting approach is not limited to enveloped viruses. We observed significant inhibition of rotavirus, a rare example of a nonenveloped yet glycosylated virus … This finding is particularly important, as it expands the scope of SCR activity beyond enveloped viruses.
“Our promising in vivo efficacy and toxicity findings lay the groundwork for further studies to evaluate these compounds as potential prophylactics and therapeutics.”
The researchers now plan to test the SCRs in clinical trials.
“This is the kind of antiviral tool the world urgently needs,” says Braunschweig.
“If a new virus emerges tomorrow, we currently have nothing to deploy. These compounds offer the potential to be that first line of defence.”
The authors suggest that SCRs may also have therapeutic implications outside of viral disease, such as in combating cancer, immunological disorders and bacterial diseases, where N-glycans also play important roles.