Novel Antiviral Targets Viral Methyltransferases

In this engaging episode of the Deep Dive, two passionate science enthusiasts explore groundbreaking research into a new class of antiviral drugs that target viral methyltransferases. Moving beyond familiar treatments like Paxlovid, they discuss how these novel antivirals could potentially combat a wide range of viruses, from COVID-19 to Ebola and dengue. The hosts break down complex concepts with warmth and clarity, explaining how viruses use methyltransferases as a "disguise" to evade our immune system and how targeting these enzymes could revolutionize our approach to treating viral infections. They thoughtfully explore not just the science, but also the broader implications for global health, pandemic preparedness, and the future of medicine. Join them for an illuminating conversation that makes cutting-edge research accessible while capturing the excitement and promise of this potential medical breakthrough.

Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase
https://www.nature.com/articles/s41586-024-08320-0

A Novel Class of Antivirals Targets Enzymes Common to Many RNA Viruses
https://www.technologynetworks.com/biopharma/news/a-novel-class-of-antivirals-targets-enzymes-common-to-many-rna-viruses-394223

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Transcript

0:24

Welcome back everyone to the Deep Dive. Ready to dive into some more cutting-edge research? Always. Great. Today we're going to be talking about antiviral research. Okay. But we're going way beyond Pax Lovid. You know Pax Lovid, the one that's been- Right. Everyone's been talking about for a while. You actually sent over this really fascinating article about a totally new type of antiviral. And honestly, after reading it, this stuff has the potential to completely change how we fight viruses. Ooh, it's pretty amazing. Yeah. And we're not just talking about COVID-19 here. Think Ebola, dengue. Right. Even some DNA viruses like those in the pox family. Yeah. What's really interesting is that this new antiviral works in a totally different way than Pax Lovid. Okay. So Pax Lovid has been pretty effective so far, but the idea that these viruses could become resistant to it is a little concerning. Yeah. That's a legitimate concern with any antiviral, really. That's why it's so important to have a variety of treatment options available. Okay. That makes sense. So let's talk about this new research. Your article mentioned a study that came out of the Tushel Laboratory at Rockefeller University. Yes. What exactly did they- Well, they discovered a completely new class of antivirals, and these target something called methyl transferases. Methyl what now? Yeah. It's a mouthful. Can you break that down for me? What are methyl transferases and why should we care about them? Okay. So think of RNA viruses. Okay. Like the ones we've been talking about, like they're masters of disguise. Uh-huh. Right. So they have these things called methyl transferases that they use to modify their RNA caps. And you can think of RNA caps kind of like little hats on their genetic material. Okay. And these modifications, they help the viruses blend in with our own cells. So it's harder for our immune system to spot them as these invaders. So they're putting on a disguise to sneak past our defenses. Exactly. And these modified caps, they don't just help them hide from our immune system. They also help the virus become more stable and make more copies of itself, which is how the infection spreads. So these viruses are pretty sneaky. I had no idea. They're very clever. Yeah. So this research focused on blocking these viral methyl transferases. Yes. How is that different from how most of the antivirals work right now? So most of the antivirals that we have, like Paxlovid, for example, they target viral protease. Okay. And these are enzymes that the viruses use to break down proteins. This new approach, it goes after a totally different target. Gotcha. So why is this new approach such a big deal? What are the advantages of going after Right. this different target? Well, for one thing, if you attack a virus with two drugs that target different parts of the virus, it's much, much harder for the virus to develop resistance. So if you combine a protease inhibitor like Paxlovid with a methyl transferase inhibitor, you could potentially have a very powerful way to fight back against these viruses. So it's like a double whammy. Yeah. Hit it with one. Exactly. You've got two different mechanisms of action. But the virus is going to have a hard time keeping up. That makes sense. And the other good thing about targeting methyl transferases is that the viral ones are structured differently than the ones we have in our bodies. So drugs that target the viral methyl transferases are less likely to have side effects. That's always good news. Fewer side effects are always good news. Yeah. So how did the scientists even discover, or how did they find this antiviral in the first place? So they started with an enormous screening of over 430,000 different compounds. Wow. To see which ones would actually block this SARS-CoV-2 methyl transferase. That's mind-blowing. So did they just throw everything at the wall and see what stuck, or was there a more targeted approach? It was a very targeted approach. Okay. Imagine trying to find a specific key for a very particular lock. They had to design and test compounds that could specifically interact with that methyl transferase and actually inhibit its function. That's really incredible. So what were the results of these mouse studies? Was it effective? So the mouse studies were incredibly promising. Okay. The new compound that they tested was actually just as effective as Paxlovid in treating COVID-19 in mice. Wow. And get this, it actually worked even when they used a mutated version of the virus. That's amazing. So this means we could potentially have a drug that's effective even against those variants. It's a big deal because that's one of the big concerns with antivirals is that the viruses are constantly mutating. So to find something that's effective against even mutated versions is very exciting. Yeah. But this isn't something we're going to see at the pharmacy next week. Not quite yet. All right. It's important to remember that this is still early stage research. It's not ready for human testing yet. Okay. So what are the next steps then? What needs to happen to actually get this into a human trial? So the first thing they need to do is make sure that this compound is stable and what we call bioavailable enough for humans. Okay. Basically, they need to make sure that our bodies can absorb it properly and it doesn't break down too quickly. And bioavailable just means that it's actually getting... How much of the drug is actually reaching your bloodstream? Okay. And is it available to do its job after you take it? If a drug has really low bioavailability, a large portion of the dose might be lost when it's digested or metabolized. So it's not going to be as effective. That makes sense. Yeah. So stability and making sure it gets to where it needs to go in the body. Right. What else? They also need to partner with a pharmaceutical company to actually help with the clinical trials. Yeah. And eventually to bring the drug to market because that's a big part of turning a promising compound into an actual treatment that people can use. Yeah, absolutely. And in your article, you mentioned that this research could have implications beyond just COVID-19, right? Absolutely. So they are looking at inhibitors for RSV, dengue, Zika, even monkeypox. Mm-hmm. And get this, they're even exploring possible applications for fungal infections. Really? Yeah. Wow. So this could be... There are a lot of possibilities. Huge for so many diseases. This is really groundbreaking research. Before we move on to some bigger picture questions, just to recap for our listener, what are the key takeaways here? Okay. So we learned about a totally new type of antiviral... Yes....that targets a different part of the virus compared to what we already have, like Pax lovid. And the initial studies show that it's very, very promising, especially since it worked against these mutated versions of the virus, which is a big concern, right? Right. And although it's really early, this research could have implications for a whole range of diseases. Yeah. That's a great summary. I'm curious, how do you even begin to translate these findings from mice to humans? Because mice and humans are pretty different. Yeah. That's a really great question. Yeah. And it's one of the biggest challenges in drug development. Just because something works in a mouse doesn't necessarily guarantee that it's going to work the same way in a human. Our bodies process drugs differently. Our immune systems are different. Yeah. There are just a lot of variables that can affect how a drug is going to perform. Right. So how do scientists actually bridge that gap? What are the next steps after the mouse studies? So it's a multi-step process. After they have these really promising results in the animal models, researchers typically do what's called preclinical studies. Okay. And these involve more detailed testing in the lab to really understand the drug's safety, its efficacy, how it's absorbed and metabolized in the body. And then if the preclinical studies look good, the next step is to move on to human clinical trials. That makes sense. It's a long process. It's a long road. And it's rigorous. Speaking of human trials, what are some of the key challenges that are involved with actually conducting human trials for a new antiviral like this one? Oh, there are a lot of challenges. First of all, you have to recruit enough volunteers who actually meet the criteria for your study. That can be difficult. It can take a lot of time. And then you need to make sure that your trial is conducted ethically, that it's scientifically rigorous, that you have the proper controls in place, that you have these blinding procedures to minimize bias. And then of course, there are always safety concerns when you're testing a new drug in humans. It sounds like a complex undertaking. It is very complex. And it's important to remember that even after all of that, there's no guarantee that the drug is going to be successful. A lot of promising drugs actually fail during clinical trials because of unexpected side effects or just a lack of efficacy in humans. Right. Right. This research has really sparked a lot of interesting questions, a lot of interesting discussion. What are some of the other things that we should be thinking about as we kind of dive deeper into the implications of this new class of antivirals? Well, one thing that comes to mind is the potential impact that this could have on the pharmaceutical industry. If this research leads to these really effective broad spectrum antivirals, it could significantly disrupt the market for these antiviral drugs. Right. That's a really interesting point. So how do you think the industry would react to that kind of disruption? It's hard to say for sure. But there would likely be a lot of interest and investment in this new class of drugs. I mean, pharmaceutical companies are always looking for new and innovative treatments. And this research could be a real game changer. Yeah. It's almost like a new frontier is opening up in the world of medicine. What other areas of research do you think might be impacted by these findings? Well, one area that comes to mind is vaccine development. One of the big challenges with vaccines is that viruses mutate. Sometimes that makes the vaccines less effective. But if we have these really effective broad spectrum antivirals available, it could potentially reduce the pressure on the viruses to mutate. Oh, interesting. Which could make vaccines more effective in the long run. Yeah. It's almost like a one-two punch. Exactly. Vaccines to prevent... Prevention and treatment. And then if you do get it, you have the broad spectrum antivirals to treat it. This really could be a paradigm shift in how we approach viral diseases. Yeah. What other exciting possibilities do you see on the horizon? Well, one of the things that I'm really excited about is the potential for personalized medicine. Yeah. As we learn more and more about how different people respond to different drugs, we could potentially tailor these antiviral treatments to an individual's specific genetic makeup and even to the specific characteristics of the virus they're infected with. That's incredible. It's like precision medicine, even more targeted. Taking it to a whole new level. And speaking of those individual responses, I'm curious how this new class of antivirals might affect people differently. Yeah. Are there any potential differences in how they might work in different populations? That's a really important question. And it's something that researchers are going to have to investigate really carefully during those clinical trials. We know that people can metabolize drugs differently based on their age, their genetics, even their microbiome. So it is possible that this new antiviral might be more or less effective in certain populations, or it might have different side effect profiles. Yeah. So that's something that they'll definitely be looking at. So it sounds like there's still a lot to learn. Oh, absolutely. But this is definitely a research area with huge potential. Enormous potential. Before we wrap up this part of our deep dive, I just want to emphasize one thing for our listeners. Yeah. We've been discussing a lot of really exciting possibilities here, but it's important to remember that this research is still in its early stages. Absolutely. It's very early. The initial results are really promising, but we need to be cautious and wait for the results of further research, especially those human clinical trials, before we can make any definitive conclusions. It's important to approach these findings with a healthy dose of scientific skepticism. Yes. And really let the evidence guide us. Exactly. Let the data speak. Well said. So for our listener, hold on to your hats because we're about to delve even deeper into this research in the next part of our deep dive. Get ready. Thinking about the potential impact on drug development, one thing that struck me is how this new antiviral could really change the game when it comes to future pandemics. Yeah. That's a really important point. Being able to target a mechanism that's common to so many different viruses, I mean, that's incredibly powerful. Yeah. Imagine having a treatment ready to go, something that could be used quickly against a brand new virus. Right. That would completely change how we respond to outbreaks. It's almost like having a universal weapon against viruses. Well, maybe not universal, but definitely much broader than anything we have right now. Yeah. This research opens up the possibility of developing a whole arsenal of antivirals, ones that target these methyltransferases. We could have specific ones for different families of viruses. Okay. Or even these broad spectrum antivirals that could target a whole range of pathogens. That's incredible. Makes you wonder what other scientific breakthroughs are just around the corner. Right. But it also raises some pretty big questions, doesn't it? Like, how would this affect the way we approach public health on a global scale? Absolutely. If we have effective broad spectrum antivirals available, do we still need to invest so heavily in developing new vaccines for every single virus that emerges? Or could we maybe shift some of those resources toward other public health priorities? That's a really thought-provoking question. It makes you realize how interconnected everything is. It really does. What about the potential impact on healthcare systems? Could this type of antiviral change how we manage outbreaks and pandemics? Potentially, yes. Having these effective treatments available, especially if they can be given early on in the course of the disease, could really reduce the burden on healthcare systems during outbreaks. Okay. That makes sense. Early intervention is always key. It's crucial. But it also makes me think about access and distribution. Would these new antivirals be available to everyone? Or would we see these disparities in access like we do with so many other medications? Yeah, that's a critical question. Making sure that everyone has equitable access to any new treatment, that's absolutely crucial. And it's something that needs to be addressed from the very beginning. You have to think about things like manufacturing capacity, affordability, distribution networks to make sure that these antivirals actually get to the people who need them, regardless of where they live or their economic status. It sounds like there are a lot of logistical and ethical challenges to consider, along with the scientific advancement. Absolutely. What about the impact on viral evolution itself? If we start widely using antivirals that target these methyltransferases, could we be pushing viruses to evolve in unpredictable ways? That's a really fascinating point. And it's something that researchers are actively studying. Viruses are constantly evolving. And using any antiviral can potentially lead to those resistant strains emerging. It's like an arms race. Right. We develop these new weapons and the viruses find ways to adapt and evade them. It makes you realize how complex our relationship with these viruses really is. It is complex. It's not just about fighting them off. It's also about understanding them, finding ways to coexist. Exactly. Viruses are a natural part of our world. They actually help to shape ecosystems and even influence our own evolution. It's important to remember that not all viruses are harmful. That's right. Some can even be beneficial. Absolutely. Some viruses are being used in gene therapy to deliver therapeutic genes to cells. Wow. And there's a whole field of research exploring the potential of viruses to fight cancer. Yeah. So while this new antiviral research is incredibly promising, it's important to remember that it's just one piece of a much bigger puzzle. It is. We need to take a more holistic approach to dealing with these viruses, one that involves research, prevention, treatment, and a deep understanding of their role in the world. Exactly. Finding that balance. Yeah. Finding that balance. Between developing new tools to fight viruses and understanding their place in the natural world. And one of the things that I find really exciting about this research is that it has the potential to help us move toward that balance. By understanding the fundamental mechanisms that viruses use to replicate and spread, we can develop more targeted and effective treatments. And that could help us reduce the impact of viral diseases on human health and the environment. Absolutely. It's about understanding the enemy, right? So we can fight it more effectively. Yeah. That's a great way to put it. So for our listeners, as we continue to dive deep into this groundbreaking research, keep in mind that while the possibilities are truly exciting... We are very exciting. It's important to approach these findings with a balanced perspective. Right. Recognizing both the potential benefits and the challenges that lie ahead. Speaking of challenges, what are some of the biggest hurdles you see in translating this research from the lab to real-world applications? Well, one of the biggest hurdles is just the complexity of the science itself. Developing safe and effective antivirals, it's a very challenging process. It often takes many years of research and development before a new drug is ready for the market. What are some of the specific challenges involved in developing these antivirals compared to, let's say, antibiotics? Well, one key difference is that viruses are much simpler organisms than bacteria, and they rely heavily on the machinery of the host cell to replicate. So finding drugs that can target those viral processes without also harming the host cell, that can be really tricky. Okay. That makes sense. So it's almost like walking a tightrope, trying to find that sweet spot where you're targeting the virus effectively, but not causing any harm to those human cells in the process. It is a balancing act. Are there any other factors that make antiviral development particularly challenging? Yes. Another big challenge is just how rapidly many viruses mutate. We've talked about this. They can evolve really quickly, and that can lead to those drug-resistant strains emerging, which can make even the most effective antivirals useless over time. It's that arms race again. It is. It's a constant back and forth. We're constantly trying to stay ahead of these evolving viruses. How do scientists even begin to address this challenge of viral mutation? Well, one approach is to develop antivirals that actually target multiple viral proteins or processes. That can make it harder for the virus to develop resistance because it would need to acquire multiple mutations at the same time. So multiple mutations at once to evade that drug. Yeah. It's like a multi-pronged attack. You're hitting the virus from different angles, making it much harder to escape. What other strategies are being explored to combat this drug resistance in viruses? Another really promising strategy is to develop drugs that target the host cell proteins that are essential for viral replication. This approach can be particularly effective against those rapidly mutating viruses because the host cell proteins, they're much less likely to change over time. So instead of targeting the virus directly, you're essentially cutting off its supply line. Yeah. You're preventing it from using our own cells to replicate. Okay. That's really clever. It is a clever strategy. What are some of the challenges with developing those types of drugs, the ones that target host cell proteins? Well, one of the biggest challenges is making sure that the drug doesn't interfere with the normal function of the host cell. You want to target those specific proteins that are being hijacked by the virus without disrupting any essential cellular processes. Right. It's a delicate balancing act. It is. How do researchers identify those specific host cell proteins that are so crucial for viral replication, but not essential for that normal cell function? It involves a whole bunch of really sophisticated laboratory techniques. Okay. Things like genetic screening, proteomics, high throughput screening of drug candidates. Researchers are constantly developing new methods to identify these potential drug targets and to test the safety and efficacy of new compounds. It sounds like there's a lot of really cutting edge science- There is. Involved in all of this research. It's amazing to see how far we've come- It is amazing. In understanding these viruses and developing new strategies to combat them. Yeah. And I think it's important for our listeners to understand that while we've been focusing on the scientific aspects of all of this research, there are also some really significant economic and social implications to think about as well. Absolutely. The development and distribution of new antiviral drugs can have a huge impact on healthcare systems, global economies, even international relations. Right. It's all interconnected. For example, if we were to develop an effective broad spectrum antiviral that could be used against a whole bunch of different viruses, it could revolutionize the way we approach pandemic preparedness. Exactly. Having a treatment that's readily available, something you can deploy very quickly against a new virus- Right. That could significantly reduce the impact of future pandemics- Yeah. Both in terms of lives lost and the economic disruption. That's a really powerful thought. It's almost like we're talking about a paradigm shift in global health. But like any major technological advancement, there are also some potential downsides to consider, right? Of course. One concern is that these powerful new drugs could be misused or overused. Okay. You know, if they become widely available, there's a risk that they could be overprescribed- Right. Which could lead to drug resistant strains emerging- Just like what we've seen with antibiotics. Exactly. It really highlights the importance of responsible drug development and stewardship. Yeah. We need to make sure these new antivirals are used appropriately and that we have systems in place to monitor for that resistance emerging. Absolutely. And it's not just about overuse. There's also the potential for these drugs to be used as bioweapons or for other malicious purposes. That's a chilling thought. Any powerful tool can be used for good or for evil. Exactly. It's a double-edged sword. So it's really important to have those ethical guidelines and regulations in place to govern the development and use of these new technologies. It sounds like there's a lot to think about- A lot to consider. Beyond just the science. This research is raising some really profound questions about how we manage these emerging technologies, how we balance innovation with safety- Right. And how we ensure that these advancements benefit all of humanity. It really highlights the need for open and honest dialogue between scientists, policy makers, ethicists, and the public to make sure that we navigate these really complex issues thoughtfully and responsibly. This has been such a fascinating conversation. I feel like we've barely scratched the surface of all the implications- Just the tip of the iceberg. Of this new class of antivirals. There's so much more to explore. Before we move on to the final part of our deep dive, where we explore some of the potential applications of this technology, I just want to leave our listener with one final thought. As we've discussed, this research is still in its early stages, but the possibilities are truly remarkable. They are remarkable. And it really highlights the incredible power of scientific inquiry and the human spirit of innovation when faced with these global challenges. It's inspiring, really. What are your thoughts on what the future holds for this new class of antivirals? I'm incredibly optimistic. I think this has the potential to really revolutionize how we treat and prevent viral diseases. And I'm so excited to see how it shapes the future of medicine and global health. That's a great note to end on. So for our listeners, stay tuned for the final part of our deep dive, where we'll explore some of the potential applications of this research and delve deeper into what the future may hold for this really exciting new frontier in antiviral therapy. So we've talked about this new class of antivirals working against so many different viruses. But what about the possibilities even beyond the ones we've already mentioned? What are researchers looking at? What are they excited about? Well, one area with a lot of potential is using them to treat chronic viral infections. OK. Like HIV or hepatitis C. Yeah. These are viruses that just linger in the body for a really long time. Right. Years or even decades. Yeah. And the treatments we have now often have side effects. Yeah. And there's always the risk that the virus will become resistant to them. Right. So could this new approach be like a safer or maybe a more effective option for people who are living with these chronic infections? That's definitely the hope. OK. Researchers are looking into whether targeting the methyl transferases in these viruses could be the key to new treatments. Ones that are more powerful or have fewer side effects, or maybe even ones that can get around that drug resistance that we see. That would be huge for millions of people. Right. What about combining these antivirals with other therapies? Yeah, that's another really exciting area. OK. For example, scientists are exploring whether combining methyl transferase inhibitors with the antiviral drugs we already have... OK....could boost their effectiveness or maybe even prevent resistance from developing. So it's like a one-two punch. You're hitting the virus from different angles. Yeah. You're basically making it much harder for that virus to survive. OK. What other combinations are they looking at? Well, there's a lot of interest in combining antivirals with immunotherapy, which uses your body's own immune system to fight the disease. Yeah. So the idea is if you weaken the virus with the antiviral first... OK....it makes it easier for your immune system to do its job. It's like you're giving the immune system an advantage. Exactly. You're giving it a boost. Yeah. What about using these antivirals to prevent infections? That's a really interesting thought. Yeah. Could we use them to protect people who are at high risk? OK. Like health care workers or people traveling to places with outbreaks? I mean, I guess that brings up a lot of questions about whether that's ethical and how you would actually do it on a large scale. Definitely. But it's an idea worth exploring. It is. As we wrap up this deep dive... Yeah....I'm just curious what you think the bigger impact of this research will be on the field of medicine as a whole. I think this research is a big shift in how we think about fighting viruses. OK. We usually just react. We wait for a new virus to show up and then we try to come up with a treatment or a vaccine. Right. But now we're moving towards something more proactive. We're developing a better arsenal and a deeper understanding of how to really attack viruses. So instead of always being on the defense... Right....we're taking a more offensive approach. Exactly. We're going after them. And that has implications for treating the viruses we know about... Yeah....but also for those future pandemics. Yeah. If we can understand these basic viral mechanisms... Right....we can create these broad spectrum antivirals that could work against a whole range of viruses, even ones we haven't even seen yet. It's like we're preparing for the unknown. Yeah. Like we're building a shield for the future. I like that as we finish this deep dive. Yeah. I want our listeners to feel that sense of wonder and possibility. Definitely. This research shows how creative people can be and it makes me feel hopeful that we can tackle even the biggest challenges. It's a good feeling. What do you think the future holds for this new type of antiviral? I'm really optimistic. I think it could completely change the way we treat and prevent these viral diseases. I'm really excited to see what happens next. It's a great way to end the episode. Thank you so much for taking us on this journey. It was my pleasure. It is fascinating to learn about these new discoveries and talk about the possibilities. And for our listeners out there, thank you for diving deep with us. We hope this made you curious and inspired you to keep learning about science. Keep asking those questions. Yeah, and until next time, keep diving deep.