Targeting a human protein can stop the Ebola virus
LA JOLLA, CA—To treat Ebola virus infections, researchers are looking closely at a key component of the virus: the polymerase
Polymerase is a viral protein that directs how the Ebola virus replicates its genome when it infects new hosts. Drugs that target the polymerase could potentially treat Ebola virus infections and save lives.
Now, scientists from La Jolla Institute of Immunology (LJI) and Scripps Research found a promising strategy to stop the Ebola virus polymerase. The researchers found that the Ebola virus polymerase hijacks a cellular protein called GSPT1. Their investigation reveals that an experimental drug that targets GSPT1 for degradation can also stop Ebola virus infection in human cells.
“To target the virus, we need to know what tools it uses,” explains President and CEO of LJI Erica Ollmann Saphire, Ph.D.who co-directed Cell Reports study with Scripps Research Professor Juan Carlos De La Torre, Ph.D., and University of Texas Medical Branch (UTMB) Professor Alexander Bukreyev, Ph.D.
Problems with Ebola polymerase
Many viruses code for their own polymerase. In fact, antiviral therapies designed to treat viruses such as hepatitis C (Sofosbuvir/SOVALDI→) act by blocking the viral polymerase.
But targeting the Ebola virus polymerase has proven difficult. In 2018, researchers tested a broad-spectrum antiviral candidate called remdesivir/VEKLURY→, which acts as a decoy nucleotide to incorporate into the viral RNA genome and shut down the viral polymerase. Unfortunately, in a phase 3 clinical trial, treatment with remdesivir did not make a difference in the mortality of patients with Ebola virus disease.
The major challenge in developing drugs directly against the Ebola virus polymerase is that scientists have not solved its atomic structure. Without this information, researchers cannot move forward with structure-based drug design.
For the new study, Fang and his colleagues tried a new strategy. Instead of directly targeting the Ebola polymerase, the researchers aimed to target the cellular proteins essential for the functioning of the viral polymerase.
“We were trying to identify the population of cellular proteins that interact with this essential virus-encoded machinery,” Fang says.
Catch the polymerase in the act
The team found that the polymerase succeeds by biding its time in host cells.
Early in infection, host cellular proteins appear to be in defense mode against Ebola virus polymerase and viral genetic material. “This presents additional hurdles for the polymerase,” Fang says. “The polymerase navigates this complex and hostile intracellular environment while concentrating on its main task: to create abundant copies of viral genomes and mRNA.”
The team discovered two cellular proteins, called GSPT1 and UPF1, that interact with the Ebola virus polymerase and limit the Ebola virus to the onset of infection. The immune system fights back.
But then comes the plot twist. Later in infection, the Ebola virus polymerase gains a foothold in cells by hijacking a subset of cellular proteins from the host’s antiviral line of defense to promote viral replication. “To our surprise, the Ebola virus can reverse the host restriction imposed by GSPT1 and UPF1,” Fang said.
The researchers found that the Ebola virus polymerase harnesses the host protein GSPT1 to upregulate viral transcription, a process the virus uses to convert its genetic material into instructions for making viral proteins.
“You can imagine GSPT1 acting as a stop sign to inform the polymerase to stop precisely at every intersection. Without the stop sign, viral transcription no longer follows the correct order, which negatively impacts the production of viral proteins,” says Fang.
“We didn’t expect to see this,” Fang says. “The virus hijacks this protein and makes it do something different from its normal job in cells. To our knowledge, this is the first time that GSPT1 has been linked to a viral infection.”
This information was made possible thanks to an enzyme, called split-TurboID, which is a biotin ligase designed by the laboratory of Professor Alice Ting, Ph.D. of Stanford University. This special enzyme, when fused to the Ebola virus polymerase, allows the polymerase to add a molecular tag to any other protein it interacts with. By searching for proteins containing this unique tag, researchers could map the complex series of interactions between the polymerase and the Ebola virus host protein.
A new pathway to interfere with Ebola virus infection
The researchers wanted to see if they could target GSPT1 to suppress Ebola infection. To test this, the LJI team teamed up with its longtime collaborator, the UTMB research group led by Professor Alexander Bukreyev, Ph.D., which could conduct experiments with live Ebola virus in a facility of high-containment research.
The small molecule CC-90009, originally developed as a drug candidate for the treatment of patients with acute myeloid leukemia, targets the degradation of GSPT1. Researchers found that treating Ebola virus-infected cells with CC-90009 interfered with viral polymerase activity and inhibited Ebola virus multiplication. Fang says follow-up research with primary cell lines and appropriate animal models should be done to provide further evidence for the reuse of CC-90009 or similar therapeutic strategies to cure Ebola virus disease.
“This study shows that there are new targets that we can target to treat Ebola virus infection,” Fang says.
Other authors of the study, “Functional Ebola virus polymerase interactomes identified by proximity proteomics in the context of viral replication,” include Colette Pietzsch of UTMB, George Tsaprailis and Gogce Crynen of Scripps Research (Florida ) and Kelvin Frank Cho of Stanford University.
The study was supported by institutional funds from the La Jolla Institute for Immunology, institutional funds from the University of Texas Medical Branch, a grant from the Donald E. and Delia B. Baxter Foundation, the National Institutes of Health (S10OD021831) and the National Institute of Allergy and Infectious Diseases (AI125626, AI128556).
DO I: 10.1016/j.celrep.2022.110544
About La Jolla Institute
The La Jolla Institute of Immunology is dedicated to understanding the intricacies and power of the immune system so that we can apply knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, not-for-profit research organization, the Institute has made many advances towards its goal: disease free life.
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Functional interactomes of the Ebola virus polymerase identified by proximity proteomics in the context of viral replication
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