Thousands and thousands of deaths and ongoing illnesses brought on by the COVID-19 pandemic have prompted scientists to hunt latest ways of understanding how viruses so skillfully enter and reprogram human cells. Urgent innovations resulting in the event of recent therapies are needed since virologists predict that future deadly viruses and pandemics may again emerge from the coronavirus family.
One approach to developing latest treatments for such coronaviruses, including the SARS-CoV-2 virus that causes COVID-19, is to dam the mechanisms by which the virus reprograms our cells and forces them to supply more viral particles. But studies have identified nearly 1,000 human proteins which have the potential to bind with viral proteins, creating overwhelming challenges in identifying which of the various possible interactions are most relevant to infection.
A multi-institutional collaboration has now developed a toolkit in fruit flies (Drosophila) to sort through the pile of possibilities. The brand 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 study, published in Cell Reports, was led by Annabel Guichard and Ethan Bier of the University of California San Diego and Shenzhao Lu, Oguz Kanca, Shinya Yamamoto and Hugo Bellen of the Baylor College of Medicine and Texas Kid’s Hospital.
“A defining feature of viruses is their ability to rapidly evolve-;a characteristic that has proven particularly difficult in controlling the SARS-CoV-2 virus,” said Bier a professor within the UC San Diego School of Biological Sciences. “We envision that this latest resource will offer researchers the flexibility to quickly assess the functional effects of things produced by this once-in-a century pathogen in addition to future naturally occurring variants.”
The researchers designed the DCR as a flexible discovery system. It features an array of fruit fly lines that produce each of the 29 known SARS-CoV-2 proteins and greater than 230 of their key human targets. The resource also offers greater than 300 fly strains for analyzing the function of counterparts to human viral targets.
“By harnessing the powerful genetic tools available within the fruit fly model system, we’ve created a big collection of reagents that might be freely available to all researchers,” Bellen said. “We hope these tools will aid within the systematic global evaluation of in vivo interactions between the SARS-CoV-2 virus and human cells on the molecular, tissue and organ level and assist in the event of recent therapeutic strategies to fulfill current and future health challenges which will arise from the SARS-CoV-2 virus and related members of the family.”
As they tested and analyzed the potential of the DCR, the researchers found that nine out of 10 SARS-CoV-2 proteins often known as non-structural proteins (NSPs) they expressed in flies resulted in wing defects in adult flies. These defects can function a basis to grasp how the viral proteins affect host proteins to disrupt or reorient essential cellular processes to profit the virus.
In addition they made an intriguing statement: certainly one of these viral proteins, often known as NSP8, functions as a form of hub, coordinating with other NSPs in a mutually reinforcing manner. NSP8 also strongly interacted with five of the 24 human binding candidate proteins, the researchers noted. They found that the human protein that exhibited the strongest interactions with NSP8 was an enzyme often known as arginyltransferase 1, or “ATE1.”
“ATE1 adds the amino acid arginine to other proteins to change their functions,” said Guichard. “One such goal of ATE1 is actin, a key cytoskeletal protein that’s 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,” she said, “and these were harking back to similar structures observed in human cells infected with the SARS-CoV-2 virus.”
Nevertheless, when flies got drugs that inhibit the activity of the human ATE1 enzyme, the consequences of NSP8 were considerably reduced, offering a path to promising latest therapeutics.
Calling their method a “fly-to-bedside” resource, the researchers say these initial results are only the tip of the iceberg for drug screening. Eight of the opposite NSPs they tested also produced distinctive phenotypes, laying the groundwork for pinpointing other latest drug candidates.
“In several cases, identification of recent candidate drugs targeting functionally essential viral-human interactions might prove beneficial together with existing anti-viral formulations corresponding to Paxlovid,” said Bier. “These latest discoveries can also provide clues to the causes of assorted long-COVID symptoms and methods for future treatments.”
The whole coauthor list includes: Annabel Guichard, Shenzhao Lu, Oguz Kanca, Daniel Bressan, Yan Huang, Mengqi Ma, Sara Sanz Juste, Jonathan Andrews, Kristy Jay, Marketta Sneider, Ruth Schwartz, Mei-Chu Huang, Danqing Bei, Hongling Pan, Liwen Ma, Wen-Wen Lin, Ankush Auradkar, Pranjali Bhagwat, Soo Park, Kenneth Wan, Takashi Ohsako, Toshiyuki Takano-Shimizu, Susan Celniker, Michael Wangler, Shinya Yamamoto, Hugo Bellen and Ethan Bier.
Source:
University of California – San Diego
Journal reference:
DOI: 10.1016/j.celrep.2023.112842