Post by Nadica (She/Her) on Jul 17, 2024 23:09:51 GMT
Drug prevents COVID symptoms in mice by protecting mitochondria, without resistance risk - Published July 16, 2024
New findings in mice suggest it’s possible to prevent organ damage from COVID-19 with an antioxidant enzyme that protects a cell’s mitochondria without the risk of resistance.
The study that led to the discovery was conducted by scientists from the Children’s Hospital of Philadelphia (CHOP), who described their work in a July 15 article in Proceedings of the National Academy of Sciences. Their compound, EUK8, kept mice from becoming seriously ill with COVID-19 and reduced the amount of production of mitochondrial reactive oxygen species (mROS), inflammatory compounds that lead to organ damage.
“We foresee the potential for mitochondrially-targeted catalytic antioxidants to be used individually or in combination with current antivirals like Paxlovid,” Joseph Guarnieri, Ph.D., the study's first author, told Fierce in an email. “This mechanism offers a complementary approach to traditional antivirals, which directly target viral components.”
The CHOP team was part of a group that previously showed that the widespread organ dysfunction seen in patients who are severely ill with COVID-19 is linked with damage to the mitochondria, the cell's energy production center. Those studies found that SARS-CoV-2 suppresses the mitochondrial genes normally involved in mitochondrial oxidative phosphorylation (OXPHOS)—the process behind cellular energy production—and directs cells to produce more of the molecules the virus needs for replication. It does this by raising mROS levels, setting off a cascade of damaging inflammation in the process.
Evidence of this was apparent in the lungs, heart, liver and lymph nodes of people who died of COVID-19. While the suppression stopped in lung samples after the virus was cleared from the body, it carried on in their other organs—a sign of long-term damage.
In their new study, the CHOP researchers wanted to see if they could stop the virus from disrupting OXPHOS by reducing mROS levels with EUK8, a catalytic antioxidant that breaks down compounds associated with oxidative stress, like mROS. To do that, they developed a mouse model that expresses the gene for ACE2, the enzyme that SARS-CoV-2 uses as a door to enter the lungs, heart and other organs.
For the EUK8 experiments, groups of 12-week-old mice were given one of three treatments: A cocktail of substances designed to boost OXPHOS called a MitoCocktail; EUK8; or MitoCocktail plus EUK8. Comparing the MitoCocktail to EUK8 would allow them to see if it was more effective to boost OXPHOS or reduce mROS. Another group of mice received a control solution. The researchers were blind to the treatments the mice received.
A day after treatment, the mice were infected with SARS-CoV-2. At days 5, 6 and 7 post-infection, mice that received the EUK8 treatment alone lost less weight than those of any other group, including those that were given the MitoCocktail either alone or in conjunction with EUK8. The mice that received EUK8 also had lower levels of mROS, inflammatory molecules, viral proteins and signs of impaired OXPHOS in the lungs.
This suggests that reducing mROS—and not just activating OXPHOS—is an effective strategy for helping mitigate mitochondrial damage due to COVID-19, the researchers concluded. It’s also less prone to resistance because it works by making the host cell less useful to the virus.
“We believe that reducing mROS represents a superior strategy for mitigating the pathogenicity of SARS-CoV-2,” Douglas Wallace, Ph.D., a senior author of the study, said in a press release. “By modulating [circulating] mROS levels, we are rendering the host cell unfavorable for [the] viral life cycle which the virus cannot change.”
The researchers’ next major milestone will be to look at the safety and toxicity of using catalytic antioxidants like EUK8 for interventional and preventative approaches in animals, Guarnieri told Fierce. They then hope to move on to human trials, perhaps testing the compounds for both COVID-19 and long COVID. The scientists are currently working with the COVID-19 International Research team to learn the role of mitochondrial dysfunction in long COVID.
“While our initial results look promising, further research is essential to determine the efficacy and safety of these therapies in human long COVID cases,” he said.
There’s also the possibility that the approach could work for other types of viruses too. Though more research is needed on this front as well, “we anticipate that the mechanism of action identified in this study … could potentially aid recovery in other mitochondria-related illnesses,” Guarnieri said.
New findings in mice suggest it’s possible to prevent organ damage from COVID-19 with an antioxidant enzyme that protects a cell’s mitochondria without the risk of resistance.
The study that led to the discovery was conducted by scientists from the Children’s Hospital of Philadelphia (CHOP), who described their work in a July 15 article in Proceedings of the National Academy of Sciences. Their compound, EUK8, kept mice from becoming seriously ill with COVID-19 and reduced the amount of production of mitochondrial reactive oxygen species (mROS), inflammatory compounds that lead to organ damage.
“We foresee the potential for mitochondrially-targeted catalytic antioxidants to be used individually or in combination with current antivirals like Paxlovid,” Joseph Guarnieri, Ph.D., the study's first author, told Fierce in an email. “This mechanism offers a complementary approach to traditional antivirals, which directly target viral components.”
The CHOP team was part of a group that previously showed that the widespread organ dysfunction seen in patients who are severely ill with COVID-19 is linked with damage to the mitochondria, the cell's energy production center. Those studies found that SARS-CoV-2 suppresses the mitochondrial genes normally involved in mitochondrial oxidative phosphorylation (OXPHOS)—the process behind cellular energy production—and directs cells to produce more of the molecules the virus needs for replication. It does this by raising mROS levels, setting off a cascade of damaging inflammation in the process.
Evidence of this was apparent in the lungs, heart, liver and lymph nodes of people who died of COVID-19. While the suppression stopped in lung samples after the virus was cleared from the body, it carried on in their other organs—a sign of long-term damage.
In their new study, the CHOP researchers wanted to see if they could stop the virus from disrupting OXPHOS by reducing mROS levels with EUK8, a catalytic antioxidant that breaks down compounds associated with oxidative stress, like mROS. To do that, they developed a mouse model that expresses the gene for ACE2, the enzyme that SARS-CoV-2 uses as a door to enter the lungs, heart and other organs.
For the EUK8 experiments, groups of 12-week-old mice were given one of three treatments: A cocktail of substances designed to boost OXPHOS called a MitoCocktail; EUK8; or MitoCocktail plus EUK8. Comparing the MitoCocktail to EUK8 would allow them to see if it was more effective to boost OXPHOS or reduce mROS. Another group of mice received a control solution. The researchers were blind to the treatments the mice received.
A day after treatment, the mice were infected with SARS-CoV-2. At days 5, 6 and 7 post-infection, mice that received the EUK8 treatment alone lost less weight than those of any other group, including those that were given the MitoCocktail either alone or in conjunction with EUK8. The mice that received EUK8 also had lower levels of mROS, inflammatory molecules, viral proteins and signs of impaired OXPHOS in the lungs.
This suggests that reducing mROS—and not just activating OXPHOS—is an effective strategy for helping mitigate mitochondrial damage due to COVID-19, the researchers concluded. It’s also less prone to resistance because it works by making the host cell less useful to the virus.
“We believe that reducing mROS represents a superior strategy for mitigating the pathogenicity of SARS-CoV-2,” Douglas Wallace, Ph.D., a senior author of the study, said in a press release. “By modulating [circulating] mROS levels, we are rendering the host cell unfavorable for [the] viral life cycle which the virus cannot change.”
The researchers’ next major milestone will be to look at the safety and toxicity of using catalytic antioxidants like EUK8 for interventional and preventative approaches in animals, Guarnieri told Fierce. They then hope to move on to human trials, perhaps testing the compounds for both COVID-19 and long COVID. The scientists are currently working with the COVID-19 International Research team to learn the role of mitochondrial dysfunction in long COVID.
“While our initial results look promising, further research is essential to determine the efficacy and safety of these therapies in human long COVID cases,” he said.
There’s also the possibility that the approach could work for other types of viruses too. Though more research is needed on this front as well, “we anticipate that the mechanism of action identified in this study … could potentially aid recovery in other mitochondria-related illnesses,” Guarnieri said.