Biotechnology

The flying toolkit was created to investigate the infection mechanism of COVID-19

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The millions of deaths and ongoing illness caused by the COVID-19 pandemic have prompted scientists to seek new ways to understand how the virus so skillfully enters and reprograms human cells. Urgent innovation leading to the development of new therapies is needed as virologists predict that viruses and future deadly pandemics may re-emerge from the coronavirus family.

The millions of deaths and ongoing illness caused by the COVID-19 pandemic have prompted scientists to seek new ways to understand how the virus so skillfully enters and reprograms human cells. Urgent innovation leading to the development of new therapies is needed as virologists predict that viruses and future deadly pandemics may re-emerge from the coronavirus family.

One approach to developing new treatments for such coronaviruses, including the SARS-CoV-2 virus that causes COVID-19, is to block the mechanism by which viruses reprogram our cells and force them to produce more viral particles. But research has identified nearly 1,000 human proteins that have the potential to bind to viral proteins, creating a major challenge in identifying which of the many possible interactions is most relevant to infection.

A multi-agency collaboration has now developed a device on the fruit fly (Drosophila) to sort through the pile of possibilities. The new one Drosophila The COVID Resource (DCR) provides a shortcut for assessing key SARS-CoV-2 genes and understanding how they interact with human protein candidates.

Studies published in Cell Reportled 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 School of Medicine and Texas Children’s Hospital.

“The defining feature of the virus is its ability to evolve quickly — a characteristic that has proven especially challenging in controlling the SARS-CoV-2 virus,” said Bier, a professor in UC San Diego’s School of Biological Sciences. “We envision that this new resource will offer researchers the ability to rapidly assess the functional effects of factors produced by these once-in-a-century pathogens as well as naturally occurring variants in the future.”

The researchers designed the DCR as a versatile discovery system. It features a series of fruit fly lines that produce each of the 29 known SARS-CoV-2 proteins and more than 230 of their main human targets. This resource also offers more than 300 fly strains to analyze their partner function against human virus targets.

“By leveraging 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 Bellen. “We hope this tool will assist in a systematic global analysis life interactions between the SARS-CoV-2 virus and human cells at the molecular, tissue and organ levels and assist in the development of new therapeutic strategies to meet current and future health challenges that may arise from the SARS-CoV-2 virus and related family members.”

When they tested and analyzed the potential of DCR, the researchers found that nine out of 10 SARS-CoV-2 proteins known as non-structural proteins (NSP) that they expressed in flies resulted in wing defects in adults. This defect could serve as a basis for understanding how viral proteins influence host proteins to disrupt or redirect critical cellular processes to benefit the virus.

They also made an interesting observation: one of these viral proteins, known as NSP8, functions as a kind of hub, coordinating with other NSPs in a mutually reinforcing way. NSP8 also interacts strongly with five of the 24 candidate human binding proteins, the researchers note. They found that the human protein that showed the strongest interaction with NSP8 was an enzyme known as arginyltransferase 1, or “ATE1.”

“ATE1 adds the amino acid arginine to other proteins to change their function,” says Guichard. “One of the targets of ATE1 is actin, the main cytoskeletal protein present in all of our cells.” Guichard noted that the researchers found much higher than normal levels of arginine-modified actin in fly cells when NSP8 and ATE1 were produced together. “Interestingly, abnormal ring-like structures coated with actin formed in these fly cells,” he said, “and these are reminiscent of similar structures observed in human cells infected with the SARS-CoV-2 virus.”

However, when flies were given a drug that inhibited human ATE1 enzyme activity, the effect of NSP8 was greatly reduced, offering a pathway to a promising new therapy.

Calling their method a “fly to bed” 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 some cases, the identification of novel drug candidates that target functionally important virus-human interactions may 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 the long range of symptoms of COVID-19 and strategies for future treatment.”

The full co-author 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.


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