Fly Toolkit Created for Investigating COVID-19 Infection Mechanisms
[ad_1]
The comprehensive Drosophila SARS-CoV-2 resource (DCR) provides reagents to identify meaningful functional interactions between viral factors and human candidates. This mosaic composition representing the SARS-CoV-2 virus was digitally created using images from a diverse array of Drosophila experiments. Credit: Oguz Kanca
They also made an intriguing observation: one of these viral proteins, known as NSP8, functions as a type 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 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 Guichard. “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,” she said, “and 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.”
The complete 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.
Funding for the study was provided by the National Institutes of Health (grants R24OD022005-07S1, R24OD022005, R24OD031447, R24OD031447-02S1, R01GM117321,…
[ad_2]
Read More: Fly Toolkit Created for Investigating COVID-19 Infection Mechanisms