Sankar Swaminathan, M.D. chief of infectious disease at University of Utah Health Care, discusses how he came upon this chance finding, and the potential broader implications for treating other illnesses caused by herpes virus, including shingles, mono, herpes, and meningitis. Read the study in PNAS and learn more here.">

Mar 22, 2016 — Researchers have unexpectedly found that a drug that has been used for the past 50 years to treat heart failure and high blood pressure also inhibits infection by the Epstein Barr virus, which causes mono and is associated with several cancers. Lead author of the study, Sankar Swaminathan, M.D. chief of infectious disease at University of Utah Health Care, discusses how he came upon this chance finding, and the potential broader implications for treating other illnesses caused by herpes virus, including shingles, mono, herpes, and meningitis. Read the study in PNAS and learn more here.

Interview

Interviewer: A new drug to combat viral infections may have been hidden in plain sight. Up next on The Scope.

Announcer: Examining the latest research and telling you about the latest breakthroughs, The Science and Research Show is on The Scope.

Interviewer: I'm talking with Dr. Sankar Swaminathan, Chief of Infectious Disease at University of Utah Health Care. Dr. Swaminathan, you just published some interesting findings in the proceedings of the National Academies of Sciences. What did you find? How did that get started?

Dr. Swaminathan: Most people are familiar with mononucleosis or mono that Epstein-Barr virus causes. Epstein-Barr virus is also referred to as EBV. Not only this EBV caused mono, but it also in a small number of people can lead to various types of malignancies or cancers.

So the most common malignancies that are associated with EBV are Burkitt lymphoma, which is a type of malignancy at the lymphocytes. And there's also a tumor that occurs mostly in Southern China and other parts of the world called nasopharyngeal carcinoma, which is a cancer of the nose and throat. And these had been associated with EBV.

So we're very interested in studying EVB and its association with cancer. Almost all of us are infected with EBV and it's asymptomatic that is without any known symptoms. But yet in a small percentage of people, it can cause disease that's quite serious in later life.

When we started working on this project to look at compounds that could inhibit EBV replication, we didn't originally start out to look for pharmaceutical antivirals really. What we set out initially to do was to see if we could find compounds that would inhibit one particular protein that's made by EBV and this protein is called SM protein. And we've been interested in the mechanism of action, the basic research and to the function of this protein for many years.

And one of the reasons that we've been interested in this protein is that all herpes viruses whether it's herpes simplex virus or chicken pox virus, they all express a similar protein and this family of proteins is critical for virus replication. We're very interested in this essential protein and learning how it works. And so we devised an assay to look for small molecules that can inhibit the function of this protein.

Interviewer: What did you find when you did that assay?

Dr. Swaminathan: When we first started doing this assay, we had only screened a few hundred compounds. When one particular compound, in this so-called library of compounds, very clearly showed up as inhibiting the function of the SM protein. And then we tried it on cells that were actually infected with the virus and we were very gratified to find that as one might predict, those viruses could no longer replicate because they really need that SM protein to replicate.

Interviewer: So you found a drug that could work to reduce infection by Epstein-Barr virus. And what was surprising about this compound? What was it?

Dr. Swaminathan: And I'm still surprised, by in a way, because this is a drug that's been in used for 50 years and it's primarily used to increase loss of water. So it's a diuretic really and it also has effects on the heart. So it's used on people with heart failure and who have liver failure, who have abnormal fluid retention, and it causes to increase loss of free water from the body.

During all this time, nobody had ever thought to that it might have other functions like this instance, really serendipitous that we made this finding. And I think we have preliminary evidence that not only does it work on SM protein of EBV, but that it may work on other herpes viruses. So we're now actively trying to see, in fact, it's working on those similar proteins and those other viruses.

Interviewer: And what is this drug called?

Dr. Swaminathan: It's called spironolactone.

Interviewer: And so you wouldn't want to use spironolactone right now as an antiviral?

Dr. Swaminathan: No, because it is a potent diuretic and heart failure drug and has hormonal effect. So and those hormonal effects are somewhat of an undesirable side effect for use in heart failure patients, for example.

The interesting thing is that there are other very similar compounds, one of which is also used in patients. Those very similar compounds that have this diuretic function do not have the antiviral function at all from what we can tell. So that really makes us think that we can separate those two functions. We're actively working with chemists here at the University of Utah to try to make some of those derivatives and test them to see if we can separate the antiviral effect from the known effects of spironolactone.

Interviewer: So your hope is to modify this existing drug so that it only works as an antiviral and hopefully one that works against that entire class of herpes viruses. Is that right?

Dr. Swaminathan: That's exactly right. And this target is different from the current target of available drugs. Although available drugs against herpes viruses currently are directed against replication of the DNA or genetic material of these viruses. What that means is that it's one class of drugs. When you get resistance, you often have resistance to many of the drugs in the class. So we're somewhat limited once we get into problems with resistance or toxicity with this class of drugs. And so I think it would be a significant advance particularly for CMV to have another set of tools as far as fighting this virus or virus infections.

Interviewer: Is there a particular reason why doctors or patients might be excited about a new drug like this coming aboard eventually?

Dr. Swaminathan: This is all speculation, any time you have a limited or a moratorium against the particular infection or infections, it's important to try to have additional drugs. And I think another potential exciting possibility to my mind is that there's a possibility of synergy. When you have drugs that are directed against two different targets, you can help prevent the emergence of resistance, you can potentially get synergistic killing. So these are all reasons that it will be good to have additional drugs.

Sometimes you have drug intolerance or allergies. These are again why it's important to have additional tools in suppressing viral's replication.

Interviewer: I have another question that's kind of show my naÔvetÈ. When I think of medications that are used to treat infections, they're usually antibacterial medications. Do we use antiviral medications as often? If someone were to come down with mono, do we typically give them antiviral medication?

Dr. Swaminathan: That's actually not a naÔve questions. It's a very good question. The reason I think that we don't use a lot as many antivirals as antibiotic is number one, we just don't have very many effective antivirals. If I could give you an antiviral drug that would cut your cold symptoms in half or even by a third, most people would jump at the chance to take it. Now we do have some antivirals that are effective against influenza. They're not as superbly effective as perhaps we would like.

The reason that people have actually tried antivirals, available ones, for mono. The problem with mono is by the time you have symptoms, it's actually a couple of weeks after you are infected, and I think it's a dollar short and a day late. And as you know it's transmitted by saliva. It's called the kissing disease and I think it would be very hard to do at trial where you gave teenagers a drug before they kiss someone.

Interviewer: Yes. So the drug that you would be developing would probably be reserved mostly for these special situations from compromised patients, for example, where it's life threatening or . . .?

Dr. Swaminathan: Well, one of the other areas where it's commonly used actually is in drugs that are active against herpes simplex virus. Valacyclovir is one. It's used every day by people who have frequent recurrences or outbreaks of genital herpes or cold sores on their lip. So these people take Valtrex every day and this helps to decrease the incidence of symptomatic recurrences.

Interviewer: So what are your goals going forward with this project?

Dr. Swaminathan: So we would like, like I said, to make those derivatives that will not have adverse side effects due to spironolactone's known properties, we would like to . . . assuming we do manage to develop these derivatives that are strictly antiviral or preferably antiviral. Excitingly in vitro anyway, in the test tube in the laboratory, we find that spironolactone is as effective as some of the currently available drugs against EBV.

So if we can make a derivative that we think might be clinically useful, then we would hope that we could advance that into preclinical testing with the goal of getting it into a patient's trial.

And while that's not the business that we're in, it really I think is incredibly gratifying when there's some possibility that in your lifetime, you could see something that you've been working on in a laboratory actually make it to patient care.

Announcer: Interesting, informative, and all in the name of better health. This is The Scope Health Sciences Radio.