Dr Denis Shields, UCD; specialises in working out the make-up of small proteins, or peptides, that enable Covid-19 to attach to its host cell.

Small proteins that help Covid-19 infect human cells and respond to existing drug therapies have been identified by scientists in new findings that pave the way for the development of anti-Covid drugs.
Dr Denis Shields, professor of clinical bioinformatics at University College Dublin, was part of an international team of scientists that reported the research in the journal, Science Signalling.
It can take years to develop a new drug against a specific infection. That is why existing drugs – such as Remdesivir which was developed to treat Ebola – have been re-purposed to try and tackle Covid-19.
The development of a new drug against Covid-19 will take time, and won’t come quickly enough to control the current pandemic waves.
“Vaccines against Covid-19 can offer protection against the disease,” Shields says, “but we don’t yet know how long they will work for in the long-term and if too few people are vaccinated it will reduce the overall protection. So, we still need to have drugs that can stop the Covid-19 virus.”

Shields specialises in using powerful computers to work out the precise make-up of small proteins, or peptides, that enable Covid-19 to attach to its host cell, and then enter into the cell where it makes copies of itself. If the action of the peptides can be blocked, the virus is unable to get access into the cell.
In follow-on research, which has been funded by Science Foundation Ireland (SFI), Prof Marc Devocelle at the Royal College of Surgeons in Ireland will manufacture the peptides discovered by Shields.

Live virus

Dr Virginie Gautier, associate professor in virology at UCD, who is supported by the same SFI-funded project, will test the peptides in the lab against live Covid-19 virus at the Centre for Experimental Host-Pathogen Research (CEPHR). It has been upgraded to meet the stringent safety standards required for an airborne virus.

Doing research with live Covid-19 is difficult, hazardous work, but made a little easier by the fact that computer analysis by Shields has identified only those molecules that hold real drug potential.

The focus will be on designing new smaller peptide drugs against Covid-19, which are cheaper to make than many more traditional drugs, and are more chemically stable. The plan is for the drugs to be inhaled by patients rather than injected, he adds.

Until the pandemic began, the CEPHR conducted research mostly on blood-borne viruses such as HIV. However, under the guidance of Dr Gautier, it has been upgraded to a level three biosafety facility which can perform research on live, airborne respiratory viruses such as Covid-19.

There is a great deal of research ongoing into how precisely Covid-19 infects host cells, and in working out the complex steps involved.

“Covid-19 gets into the cells with the help of proteins on their surface, which it attaches to,” explains Shields. “One of these is called ACE2, and we found that the ACE2 binds to other proteins via ‘motifs’ that we identified.”

Motifs in this context, are small protein segments, he explains.

Covid-19 drugs could work in two ways to prevent infection. They could be designed to stop the virus binding to the outside of human host cells, says Shields, or they could be made with the intention of stopping viruses from moving inside the host cell after they have successfully bound to the outside of the cell.

Gautier’s team will challenge Covid-19 by seeing how it responds in the lab against a variety of drug-like substances. Those drugs that work well in the lab, will move on eventually into animal studies, which, if successful will move into human clinical trials.

“We won’t be able to test everything, so you first generate good ‘hits’,” Gautier says. “And then we’ll have to look at the one that you can practically produce as well. These drugs will have a biological impact on the cells. We need to measure that to make sure they are actually active, and they’re doing the job we want.” The scientists will be watching out for devious ways that Covid-19 might sneak into host cells. This knowledge can help them understand how viruses evolve and adapt to drugs, and to more quickly respond in future to the emergence of new virus threats.

“New drugs arising from our research will be too late for this pandemic, but may be useful in a future one,” Shields underlines.