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COVID-19 Cytotoxicity Testing by Rhodium

Episode 27: Finding a COVID Cure

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SwRI scientists have pinpointed a potential drug therapy in the search for a COVID cure. After screening millions of drug compounds using SwRI’s Rhodium software, they have narrowed down the field to one strong hit with a family of related therapies. After testing is complete, their treatment could halt the virus and save lives. A scientist on the inside explains how they sifted through millions to find the one, what new virus strains mean for their research and what must happen before the therapy can be authorized to treat COVID patients.

Listen now as SwRI Scientist Dr. Jonathan Bohmann explains the process of finding a COVID cure.


TRANSCRIPT

Below is a transcript of the episode, modified for clarity.

Lisa Peña (LP): It's a new year of breakthroughs, discoveries, and advancements. We're kicking off 2021 with an important update. SwRI scientist Dr. Jonathan Bohmann is on the front lines of life-saving COVID research. The latest on his team's work and what they've uncovered since our last discussion, that's next on this episode of Technology Today.

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We live with technology, science, engineering, and the results of innovative research every day. Now let's understand it better. You're listening to the Technology Today podcast presented by Southwest Research Institute.

Hello and welcome to Technology Today. I'm Lisa Peña. We start the new year with new hope in the fight against the coronavirus pandemic. With the U.S. death toll climbing toward 400,000, effective prevention and treatment is a top priority for the nation's scientists and researchers. Already millions have received a COVID vaccine. And there's been solid progress in finding treatments for patients already infected.

SwRI staff scientist, Dr. Jonathan Bohmann, is leading a team screening drug compounds to find potential COVID therapies. We spoke to him in April, and he's back with an update on this developing topic. Thank you for joining us, Jonathan.

SwRI Staff Scientist Dr. Jonathan Bohmann is leading a team working to find a COVID-19 cure. After screening millions of compounds, they are closely studying a drug that may prevent the virus from replicating.

Dr. Jonathan Bohmann (JB): Yes, I'm happy to be here.

LP: So I wanted to have you back because this research is really moving quickly. It seems every week there are new developments. So back in April, you started the process of screening millions of drug compounds that could potentially fight COVID. What has developed since then?

JB: Sure. So in that time, we were able to select from those millions of compounds, a subset or part of those that we predicted to be safe. And so the biggest thing, there's probably lots of compounds that could be antivirals. The only problem is that they might be also toxic. So the margin of safety - the effective dose versus tolerable dose - that's an important thing. So we attempted to predict that on a subset of compounds, and those were tested. I think we're into - we're into several hundred compounds, probably close to 700 compounds that were actually tested. And so of those, we had 40 or 50 that were very functional inhibitors, in vitro. That means in cells that were grown and then infected with - these are human cells - grown and infected with the virus. So we were able to demonstrate that these compounds were able to stop the replication of the virus.

And so like I said, there are several compounds that do that. But the most important thing is what is the amount of drugs that's required to inhibit the virus versus the amount of drug that would cause adverse effects. And so that the safety ratio. Usually you start out with a value of maybe 10. Twenty is great. We do have a couple of compounds that are - one of them is a safety factor of 200. The other one's a safety factor of 400. So that's a really amazing result. We've found a good path. We've had a great tool in Rhodium. And actually things have gone as expected.

LP: So you started with millions of compounds. You broke that down to about 700 that were the top ones you wanted to look at closer. From there that list got even smaller to about 40 or 50. And from there, from what I understand, you started safety testing. And so now you're really getting into the weeds here with really finding that exact treatment that is going to be the key, hopefully, to attacking the virus.

And you did mention safety ratings. And you mentioned that 200 to 400 was good. Can you clarify what that scale is of safety ratings? What is the area you want to get to?

JB: Right. So that's a safety factor that's done from the bioassays that we're doing. And so every drug has an amount or a concentration when it's administered that is not effective. And then as you increase the concentration, then it starts to become effective. And then if you increase that concentration too much, you might kill the cells with toxicity.

So the safety factor is how much greater is the toxic concentration than the effective concentration? So you have to have a margin of safety. So if you need to escalate the dose, you find out that later maybe you need a higher dose or being effective in an animal, which is a living, breathing system, rather than cells. So you need a wide safety margin. And so that safety margin is the ratio of this concentration.

So in other words, if I have a treatment regimen at some dose, but if I double the dose and it's toxic, that's a safety factor of 2. If I have a treatment regimen, and it works fine, and I don't have any toxic effects until I increase the concentration by a factor of 10, that's even better. So that's a safety factor of 10. Where we are right now is super important because we're at a predicted safety factor of 200, which is super important for antivirals because usually the doses end up being larger than you think. And that's so you can catch up with a viral infection that's just exploding inside of your body. So larger doses are typically required for anti-infectives, compared to normal treatments. I say normal treatments. I don't think there's a normal treatment, but ones you might find, like cancer therapeutics or even heart medications, anticoagulants.

LP: So the higher the number, the better it is because you can--

JB: Yeah, right.

LP: --increase the dosage--

JB: marginally

LP: --and know that they're safe, should the condition require higher dosing. So got it. How would you sum up what you've done in less than a year?

JB: We've gone from in that year's time not even knowing a whole lot about the virus other than the biochemical structure of this one protein. We started before people even had full structure of the spike protein. So we started that. The compounds that we had, we got through the screening of 40 million compounds in less than a month. That screening actually took less time than the actual biochemical screening that we did later. And we expected that because with the biochemical screening, you have to set up the laboratory. There's lots of people involved. There's biosafety considerations. You have to test and validate the assay before you can do any of that testing. So you have to ensure that the assay's doing what you think. So all that was being brought up while we were doing the virtual screening. And it took a little bit longer, but it took a little bit longer for everyone because it's doing the laboratory work.

So anyway, the first round of laboratory work was done in August. And that's where we found an initial set of hits. Then it took a while to get our compounds and materials supply in. And that took another few months because the library of compounds that we screened was a virtual library. We ordered those compounds we predicted to be safe. And to just obtain that material supply took a while.

So through August and September, that was being done. And finally we did a lot of assay work in a very short amount of time once everything was aligned. That was in October. And so October, November, and December is when we've done our refinement to the current compound. We'll call that a strong hit compound. And it's not an in silica hit. It's an actual candidate to carry forward into animals.

But that's what's been going on. The reality of lab work is it just takes a while. But it was good because we had in place our candidates. And had we not had the Rhodium tool, we wouldn't have known where to start with those 800 compounds. So we wouldn't have--

LP: The Rhodium--

JB: 800 compounds, just candidates. We would have been, who knows what?

LP: Yeah, Rhodium has been the key here. And I want to get to that in a moment because we did talk about that back in April. But I want to help our audience remember what exactly Rhodium is. But I do have some questions about that the compounds, these strong hits and candidates that you're seeing.

LP: Is it just one compound that's really standing out right now? Or are there a couple? Or is it just the one?

JB: There's a couple. These all happen to be very structurally-related compounds. So you could call that the lead compound, and the others are members of a family.

LP: So you've already tested it in cells. You will now move on to a living, breathing system - animals. And so how long does that process take? And how long do you think it will be until you nail down an exact treatment, for use in people?

JB: What has to happen is beyond that, we have to demonstrate safety and efficacy in a-- we call it a proof of concept study in a small animal, typically a rodent. And then there has to be a study in primates. And so that's kind of beyond what Southwest Research does. And so that's where our partners have to take the lead on that. Although we'll be involved in that program, the computational work, obviously the Rhodium part of that end, and then the length of time required for that-- I really don't want to [CHUCKLES] make a claim that we can't back up because that will involve much more deeply the other institutions that are involved. Everyone is accelerating this program. And I will say that the protocols and so forth for doing that work have been-- it takes a while to get that set up. So in anticipation of that, we have been preparing the plans for those animal tests, even before we had the compound selected. So we started doing that planning back in August. That gives you an idea of the lead time required. So--

LP: So you bring up a good point.

JB: --even though we didn't have a candidate, we had to have the plans in place for those studies.

LP: Yes. So you do bring up a good point. We do not do animal testing at Southwest Research Institute.

JB: No, we do not.

LP: So you will be working with partners on that side of things. And that is something that-- is that just a normal part of getting a drug approved, going through these types of tests?

JB: Oh, yes.

LP: Is that the--

JB: Sure.

LP: --general process? Yeah.

JB: Yeah. So it's demonstrating that this is safe and a living, breathing system. And so you never-- the important thing before you can get an emergency use authorization from the FDA-- which is how the vaccines are being rolled out, in the sense they're not approved. As far as I understand, these are all being used under an authorization for emergency use. So there's a little bit of a nuance there. But for emergency use authorization, you still have to show that there's safety there. And that's what's been done. So with these vaccines, they've been shown to be efficacious in an animal, probably a primate. And they've been shown to be safe in some safety trials, which is what you've heard about. And so as a result of doing the safety, they went ahead and just tracked whether people got infected or not. But in this case, what we have to do is show that this will likely work in a non-human primates. And then the safety still has to be done in human subjects.

LP: You are talking about the vaccine because the process is similar to what you will have to accomplish.

JB: Yes, it is. Right. That's exactly right.

LP: So it's too early, obviously, to nail down an exact timeline for rolling this out. But are you able to, at this point, identify how your stand-out compound might work in the body, how it would attack the virus, and also any sort of-- are you able to gauge right now how soon after infection treatment would be needed to be administered to be effective?

JB: That's the biggest deal. And so that's why the safety-- I don't know yet. But that's why the safety factor is so important with antivirals because the longer you wait, the higher the dose has to be after infection. So let's say with Tamiflu, the dose is fixed. And that dose only works after a--

LP: Oh, yeah a couple days within showing symptoms.

JB: --certain amount of time. And beyond that, it's too late. And there's not different doses of Tamiflu. There's one dose. One thing is the safety factor is high enough, it might be possible to-- it wouldn't happen right away, but to have the thing approved for a range of dosing, just like you see with cholesterol medication and so forth. There's a range of dosing that's available depending on the biological requirement.

And so the thinking is preliminarily, this is a viral replication inhibitor. So this main protease is part of the viral replication. It doesn't block virus entry like an antibody, but it shuts down viral replication. So the good news is compared to a vaccine, a vaccine only works for that recognition part. If you miss that window, then the vaccine doesn't necessarily do as much good. And there's probably not a lot of room. You can't go back and get a larger dose or anything like that.

With a treatment like this, the thinking is with a safety factor high enough, you would increase your time to treatment. And that is a parameter, which is how long after the initial infection can you treat? So that's time to treatment. And that actually is one of the tests that you do within an efficacy trial. And that's probably what-- I don't know when that trial will happen. Again, that's the animal work that we don't do at Southwest Research. But that would be part of it, would be to find the dose that's toxic but can be used to extend that treatment window to the longest possible. And there's obviously some limits.

LP: We are hearing about this new aggressive strain of the virus. What can you tell us about this new strain that was first found in the UK, but now it's here in the United States? Are you studying it? And does it change your research in any way?

JB: Right. And so the main...in our group of partners, the folks that are really close on the front lines of the actual medical-- what happens out in the field-- Walter Reed has the best eye on all this stuff. And the information I'm getting from them is that to the best of our knowledge, there's more than one variant. You're going to hear reports probably in the coming weeks of variants emerging. That's just natural selection, that over time what you find are viruses that spread more easily and are less lethal. So they become wider diluted in the population. So the longer that the virus spreads, you'll have these variants emerge that, because of a mutation, they'll just take over. They'll just be more effective, and the other variants won't catch up. But usually that means that the symptoms or the biological consequences are typically better in terms of the risk of death--

LP: Less lethal.

JB: --and so forth. Yeah. And they get more widely spread. I'm not going to say coronavirus will be the common cold. But things generally go in that direction. The most widely-dispersed viruses are not lethal viruses, by what we would think of as a biohazard situation. So less lethality, but more and more infectivity.

LP: So just to recap, though, what you said, generally, when viruses mutate, they become less dangerous. So the thought is coronavirus, the COVID-19, will follow this same pathway?

JB: Yeah, and that's what makes them more-- so the mutations, the virus doesn't think or do anything other than replicate. It's barely alive because it can't replicate by itself. But yeah, exactly, the ones that you're going to see more often are the ones that are more infectious. And the one where there are fewer symptoms, people are not going to-- people are going to spread the ones that show fewer symptoms or less severity in symptoms.

LP: So do these mutations--

JB: So there's going to be [frequency].

LP: So do these mutations change your research in any way?

JB: No. And this is the good news, is that those mutations, the ones that we know about, are on the spike protein, which controls viral recognition of the host cells. And our target is in the lifecycle in replication within the cell. So after a cell has been infected with the virus, then the virus multiplies. That's replication. And our treatment would interfere with the replication, not the recognition. And so the changes that are being observed are in the recognition domains of the spike protein mainly.

LP: So you've mentioned Walter Reed several times. Who else are you collaborating with to move this project forward?

JB: USAMRIID, Army Institute for Infectious Diseases, and then Texas Biomedical Research Institute, TBRI.

LP: So these institutions working together to nail down a therapy that will essentially stop the virus from replicating and to stop people from getting terribly ill and hopefully stop the increase in deaths we've been seeing. So is that the goal, obviously, here saving lives?

JB: That's exactly right.

LP: So the key, as we talked about, is Rhodium. This is where it all started with us at Southwest Research Institute. And we did talk about Rhodium last time. But I think it's definitely worth covering again. This is a software, and it's really the key to your screening process. Can you go over what Rhodium is and what it does?

JB: Sure. So Rhodium is a tool for virtual screening. And what it can do is it can find drugs that are likely to fit into the surface of a protein. And when those drugs fit into the surface of the protein, the biological process that that protein participates in would be altered. In our case, we want the process to be inhibited. So what Rhodium uses is a three-dimensional model, in this case, part of the virus. And this part of the virus is called the main protease. But you actually have a three-dimensional model of it. And that has certain locations on the-- the surface is like a terrain. And there are peaks and valleys. And some of the valleys are important functional sites. Those are called active sites. And what this drug can do is block these active sites. Or sometimes the biological process in general needs two proteins to come together. And that creates a biological signal. And one of the things we can do with Rhodium is find drugs that would interfere with that process.

So what Rhodium can do is take three-dimensional models of those target proteins and find, maybe from the list of millions of drugs, drugs that would bind to those parts of the protein that alter the biological process. So that's--

LP: And it does this--

JB: --what Rhodium does.

LP: --quickly. It's fast, huh?

JB: Yes, very quickly and fast. And so on certain types of problems, it can be 250,000 compounds a day for virtual screening. In this project, we were able to access some of the DOD's supercomputers. And we were able to do several million compounds a day. In fact, we were able to screen the 40 million compound library in quite a short amount of time. So yes, it's very fast.

LP: So as the vaccine becomes more widespread and more people receive it, will that slowly eliminate the need for a drug therapy? Or will a treatment be something needed for years to come?

JB: We're going to be with coronaviruses for a long time. They've been around. They're not going away. So there's always going to be a need for a treatment. The vaccine's not going to work for everybody. We've already seen that there are limitations on-- variations in immune response to a vaccine and variations in tolerability for a vaccine. There's some limit to what a vaccine can do. A vaccine will not be able to do to keep everyone safe and to prevent infections in the future. So there's always a need for therapeutic tools for infections.

LP: How do you describe this moment of your career? Is this the biggest research initiative of your life?

JB: In terms of the-- yeah, it's the biggest team of my life. So I guess that makes it [CHUCKLES] the biggest initiative in a sense. Yeah, and to bring so many people together with that common purpose and moving forward, it's the biggest team I've been involved with. I think in terms of impact, the impact is obvious-- it's so clear. Sometimes when you're doing a research project, you see a small part of it. But here I was able to, and am, participate in the whole thing. We were doing this-- yeah.

LP: So to wrap up, so many have lost so much due to the pandemic, loved ones, livelihoods, their stability, and I've asked you this question before, and I think it's a great time to ask again all these months later, as a scientist on the front lines of this battle, what words of encouragement do you have for our listeners hit the hardest by this virus?

JB: We think about these issues also. And all of us that are involved in the research have been personally impacted in their own lives. We were talking in our project meetings just friendly banter about people's own bubbles and not really in a scientific meeting, but I'm sure there's people that have had their families affected. And that's on everyone's mind. I'm sure of it. We're all being affected by this. And normally I think in a project, the telltale sign is you say, all right, we're looking at this project schedule, when should we do this? When should we do this? And the answer is always right now, right now, right now. We don't see that in every program. So the sense of urgency is there. Should we do this activity now? Yes. We should. There's no better time.

LP: That is encouraging because it shows us that this is of top importance. And the science is really rallying behind this research to find a cure, find a treatment, and find an end to this pandemic that's abruptly changed our lives.

JB: Yeah.

LP: Jonathan, thank you so much for this important update today. And really, thank you and your team for the work that you're doing. This work has the potential to help and heal so many people. So much great information today, again, offering hope that serious illness due to COVID can one day and will one day be prevented. So I look forward to following up with you again soon.

JB: Yes, thank you.

And that wraps up this episode of Technology Today. You can hear all of our episodes and see photos and complete transcripts at podcast.swri.org. Remember to share our podcast and subscribe on your favorite podcast platform.

Want to see what else we're up to? Connect with Southwest Research Institute on Facebook, Instagram, Twitter, LinkedIn, and YouTube. And now is a great time to become an SwRI problem solver. Visit our career page at swri.jobs.

Ian McKinney and Bryan Ortiz are the podcast audio engineers and editors. I am producer and host, Lisa Peña.

Thanks for listening.

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We offer drug discovery services from de novo biostructure based drug design with the proprietary Rhodium protein docking platform, analog synthesis, in vitro assays, quantitative structure activity relationships (QSAR), lead optimization and scale-up of drug candidates for animal modeling.