Broad spectrum antivirals: a complicated mission … but not impossible!


Between their parasitic activity and ability to mutate, viruses are difficult to target effectively with antivirals. But scientists aren’t giving up. The team of Thomas Michiels (de Duve Institute) is on a promising track to develop a broad-spectrum antiviral.

When a bacteria infects us and our body can't get rid of it on its own, resorting to antibiotics quickly gets us back on our feet. Why isn’t this the case for viruses? Why are there no ‘ready-to-use’ antivirals to deal with (new) viral infections like Covid-19? Antibiotics are to bacteria what antivirals are to viruses. A plethora of antibiotics exist to fight the different families of bacteria that can infect us. Likewise, many antivirals are developed to overcome or limit the severity of infections caused by different classes of viruses (DNA viruses, single or double stranded RNA viruses, retroviruses).

The big difference between bacteria and viruses is that the former are autonomous living organisms and the latter are made up primarily of genetic information that parasitises our cells’, Prof. Michiels says. In fact, viruses must use the machinery of our cells to multiply and infect our body. ‘Consequently, they offer far fewer potential specific therapeutic targets and the molecules directed against their activity within our infected cells risk causing collateral damage by also interfering with the machinery of our body’s healthy cells.

Disrupt production of virus genetic material

There are, however, ways to avoid collateral damage by directly attacking the ‘parts’ that make up the virus or are produced by it for its multiplication. For example, RNA viruses, such as the SARS-CoV2 responsible for Covid-19, produce their own polymerase, the necessary tool for replicating their genetic material inside our cells. This viral polymerase, which differs from that of our cells, is thus one of the targets chosen by researchers for finding antivirals with the widest possible spectrum against RNA viruses. ‘These antivirals have the effect of providing fake assemblies for the production of virus RNA by viral polymerase’, Prof. Michiels explains. ‘As the RNA virus genome fails, so does its ability to infect new cells. This is the mechanism on which ribavirin is based, used until recently against hepatitis C and the first antiviral tested against SARS-CoV2 but with a weak effect in vitro, and remdesivir, another antiviral produced previously.’ But each viral polymerase has its specificities, which means that a single molecule can’t be optimal for all RNA viruses. A promising new antiviral based on the same principle is EIDD-2801, developed just before the COVID-19 pandemic and active against several coronaviruses in vitro.

Take no prisoners

Another obstacle in the quest for a broad spectrum antiviral is virus resistance, particularly in RNA viruses which mutate very easily. As a result, every time an antiviral is developed, resistance appears. ‘Hence the interest in using several antivirals that target different stages of a viral invasion into our cells, as is the case with the hepatitis C virus or HIV, and even targeting parts of our cells which the virus uses to multiply and infect new cells, provided that this isn’t too toxic to the body’s’ functioning.’

Targeting a pattern

Prof. Michiels’s de Duve Institute laboratory is pursuing another promising route: the discovery of a highly conserved sequence on polymerases from positive RNA viruses. This means the same ‘pattern’ is present on all these polymerases and could therefore be a prime target for combating infections by this group of viruses, which include coronaviruses. The discovery of Thomas Michiels’team stems from fundamental research that remains essential to understanding the mechanisms that govern our body and viruses and their interactions. These recent results open up encouraging prospects in the fight against emerging viruses. Of course, research needs time and it takes years for findings to lead to the possibility of new drugs. But they give us both hope and new weapons to fight this type of invader in the future.

Audrey Binet


Published on April 29, 2020