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Researchers at The Chinese University of Hong Kong (CUHK)’s Faculty of Medicine (CU Medicine), in collaboration with international partners, have identified a key cellular protein, ARF4, as a potential target for the development of broad-spectrum antiviral drugs. Their findings, recently published in the international scientific journal Nature Microbiology, could provide new therapeutic strategies to combat various viral infections.

Pathogenic viruses, like SARS-CoV-2, influenza and Zika, could trigger numerous health conditions, from mild to severe. Current antiviral treatments often target specific viruses, limiting their effectiveness and leading to the development of drug-resistant strains. The discovery of ARF4 as a potential antiviral target offers a new approach. This protein is essential for the release of many different types of pathogenic viruses from infected cells. The researchers also developed an antiviral molecule, ARF4TP-4, that effectively blocks the activation of ARF4 involved in virus release. In animal studies, this molecule significantly reduced the severity of Zika and influenza infections and protected against severe disease induced by these viruses.

ARF4 acts like a traffic controller by helping translocate materials inside our cells

When viruses invade the human body, known in medicine as a host, they sneak into host cells like unwanted guests. Once inside, they take over cell’s machinery to make copies of themselves, which damages or destroys the cells. Host immune system fights back to eliminate viruses by causing inflammation, leading to symptoms like fever, fatigue and runny noses.

ARF4 acts like a traffic controller inside our cells, helping translocate materials among the subcellular compartments or ship them outside. Smart viruses take advantage of this to manipulate ARF4 so newly formed viral particles are released from infected cells, allowing them keep continuously infecting their host. In this research, CU Medicine found that when ARF4 was “abolished” or “turned off” by gene-editing technology, it stops multiple viruses like Zika, influenza and COVID-19 from spreading effectively both in cells and animal models. Mice engineered to lack ARF4 showed much less infection and organ damage from Zika and influenza viruses.

Dr Li Mingyuan, Research Assistant Professor in the Department of Chemical Pathology at CU Medicine, explained: “When a virus enters a cell, it tricks ARF4 into becoming active. Active ARF4 then helps newly formed virus particles get packaged and shipped out of the cell safely. But if ARF4 is missing or inactive, the virus gets lost inside the cell and sent to the lysosomes, the cell’s ‘recycling bin’, to be destroyed instead of released. This stops the virus from spreading and making us sick. Release is an essential step for successful infection by any virus, and ARF4 plays an important role in facilitating this process.”

Antiviral molecular ARF4TP-4 lowers the severity of Zika and influenza infections

Based on these findings about ARF4, researchers formulated and identified a new antiviral molecule, ARF4TP-4. It is expected to anchor in a groove composed of ARF4 and its activation controller, another host protein named GBF1, and lead to the failure of ARF4 activation. Although this molecule is unable to completely stop the infection, it efficiently lowers the severity of infection by limiting the release of pathogenic viruses from infected cells. Considering the biological functions of host factors in their own cellular processes, potential toxicity is a main limitation on the development of antivirals targeting host factors. The advantage of ARF4TP-4 is that ARF4 may not be irreplaceable for host, according to the current investigations. Experimental data supports this hypothesis, with ARF4 targeting peptides exhibiting minimal cytotoxicity and having been safely used in mice. Nevertheless, additional preclinical research involving nonhuman primates is imperative for delineating the dosing regimen and safety profile of ARF4-targeted therapeutics before initiating clinical trials.

“This research is incredibly exciting because it opens up the possibility of developing a single treatment that can be effective against many different viruses,” said Dr Mingyuan Li, one of the leaders of the research project. “This is particularly important given the increasing threat of new and emerging viruses and the challenge of developing effective vaccines and antiviral medications for each one.” She added that the breakthrough offers a novel strategy in antiviral drug development, with potentially wide-ranging implications for public health, and that further research is needed to bring the findings to clinical trial and ultimately make new treatments available.

Dr Li and her team are undertaking pioneering research to discover new ways to fight viruses. Her group focuses on identifying viruses dependent on key host proteins, paving the way for the development of antiviral drugs. This important research is supported by several grants, including from the National Key R&D Project of China and the National Natural Science Foundation of China (NSFC), and is enhanced by equipment support from the Li Ka Shing Translational Omics Platform.