UC San Diego researchers have collaborated on a study, published in Cell Reports, involving experiments on flies to identify pathways to new drugs to treat COVID-19 and other viruses.
“A defining feature of viruses is their ability to rapidly evolve – a characteristic that has proven particularly challenging in controlling the SARS-CoV-2 virus,” said Ethan Bier, a professor with the UC San Diego School of Biological Sciences.
One approach to developing new treatments for such coronaviruses, including the SARS-CoV-2 virus that causes COVID-19, is to block the mechanisms by which the virus reprograms cells, forcing them to produce more viral particles.
But studies have identified nearly 1,000 human proteins that have the potential to bind with viral proteins, creating overwhelming challenges in identifying which of the many possible interactions are most relevant to infection.
The collaboration, with Baylor College of Medicine and Texas Children’s Hospital, both in Houston, has developed a toolkit using fruit flies (Drosophila) to sort through the possibilities. The new Drosophila COVID Resource (DCR) provides a shortcut for assessing key SARS-CoV-2 genes and understanding how they interact with candidate human proteins.
The goal, researchers said, is for the new resource to allow teams to assess factors produced by “this once-in-a-century pathogen as well as future naturally occurring variants.”
The team designed the DCR as a versatile discovery system. It features an array of fruit fly lines that produce each of the 29 known SARS-CoV-2 proteins and more than 230 of their key human targets. The resource also offers more than 300 fly strains for analyzing the function of counterparts to human viral targets.
“By harnessing the powerful genetic tools available in the fruit fly model system, we have created a large collection of reagents that will be freely available to all researchers,” said Hugo Bellen, from Baylor College of Medicine and Texas Children’s Hospital.
The tools, he added, will aid in “the systematic global analysis of in vivo interactions between the SARS-CoV-2 virus and human cells at the molecular, tissue and organ level,” while helping in the development of new therapeutic strategies to confront SARS-CoV-2 and its variants.
As they tested and analyzed the potential of the DCR, the researchers found that nine out of 10 SARS-CoV-2 proteins known as non-structural proteins (NSPs) resulted in wing defects in adult flies. These defects can serve as a basis to understand how the viral proteins affect host proteins and benefit the virus.
One development in particular intrigued the researchers. A viral protein known as NSP8 functions as a type of hub, coordinating with other NSPs. It also strongly interacted with five of the 24 human binding candidate proteins, the team noted. They discovered that the human protein that exhibited the strongest interactions with NSP8 was an enzyme known as arginyltransferase 1, or “ATE1.”
“ATE1 adds the amino acid arginine to other proteins to alter their functions,” said Annabel Guichard, a researcher from UC San Diego. “One such target of ATE1 is actin, a key cytoskeletal protein that is present in all of our cells.”
Guichard noted that the researchers found much higher levels of arginine-modified actin than normal in fly cells when NSP8 and ATE1 were produced together.
“Intriguingly, abnormal ring-like structures coated with actin formed in these fly cells,” Guichard added. “These were reminiscent of similar structures observed in human cells infected with the SARS-CoV-2 virus.”
However, when flies were given drugs that inhibit the activity of the human ATE1 enzyme, the effects of NSP8 were considerably reduced, offering a path to promising new therapeutics.
Calling their method a “fly-to-bedside” resource, the researchers say these initial results are just the tip of the iceberg for drug screening. Eight of the other NSPs they tested also produced distinctive phenotypes, laying the groundwork for pinpointing other new drug candidates.
“In several cases, identification of new candidate drugs targeting functionally important viral-human interactions might prove valuable in combination with existing anti-viral formulations such as Paxlovid,” said Bier. “These new discoveries may also provide clues to the causes of various long COVID symptoms and strategies for future treatments.”
Funding for the study was provided by the National Institutes of Health, the Kyoto Institute of Technology, the Tata Trusts in India to the Tata Institute for Genetics and Society at UC San Diego, Jan and Dan Duncan Neurological Research Institute at Texas Christian Hospital, and a CAPES fellowship.
– City News Service
