HIV/AIDS Research: Its History & Future Meeting
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Ray Schinazi: Thank you Bob [Gallo]. Thank you for inviting me and the rest of the gang. It's a pleasure to be here. I think that last time I was at Cold Spring Harbor, I was about 32 years old at a herpes meeting many moons ago. It's nice to be back and—

Bob Gallo: It's great to have you. Thank you also to John [Coffin] and Bruce [Walker] because it was [unintelligible 00:00:14].

Ray: Yes, well, I said the rest of the gang as well, but I know you are the driving force.

[laughter]

Ray: Anyway, I want to say that [00:00:30] my research really rests on the laurels of many people who have contributed immensely to the field of HIV. Some of them have spoken before me and some of them will speak after me. I'm really delighted to be here and tell you about my experience in antiretroviral agents. It all started many moons ago. I started my career as an organic chemist working on anti-cancer drugs, and then I was transported across the pond [00:01:00] thanks to Bernard Roizman and my dear uncle, André Nahmias, who was a herpes virologist.

I worked in the laboratory of Bill Prusoff (1920–2011). I didn't even know how to draw the structure of a nucleoside when I arrived in the United States. Bill was an exceptional leader, probably the grandfather of antiviral agents, and the man who actually discovered, made in 1959, 5-iododeoxyuridine. Some of you may remember this drug, it's the first [00:01:30] FDA-approved antiviral drug for herpes keratitis. Working with Herb Kaufman at Louisiana at the time with rabbits infected in the eye and then, of course, humans.

This was truly the very first antiviral agent with some selectivity. It wasn't totally selective. I had the pleasure, also, of getting to know the people at Burroughs Wellcome, especially Gertrude B. Elion (1918–1999), who won the Nobel Prize in Physiology and Medicine in 1988. She said, "It's amazing [00:02:00] how much you can accomplish when you don't care who gets the credit." Her work really epitomized that because she shared reagents with me, whether I need MTA's (material transfer agreements) or CDA's (confidential disclosure agreements) or anything, to be able to do work. She would send me dry powder to try, including acyclovir to work in my lab, and being able to work on combination chemotherapy for herpes virus infections.

I worked with Andy and Larry Corey and others on the first study in humans, [00:02:30] with Dannie King and others, finding out that acyclovir could be useful for genital herpes, and that was a really big breakthrough. Of course, there's been many renditions of aciclovir going forward, thanks to the work of [Jan] Balzarini and others, making it more orally bioavailable, valaciclovir. Again, fine-tuning these drugs have made a big difference in terms of the amount of drugs that you have to give people who are infected.

Of course, [00:03:00] these drugs are extremely effective and have been very successful. I am really very pleased that I got involved in antivirals because that was a terrific launching pad, having worked with both Bernard and worked with Andy and Bill Prusoff and some of the giants in the field of virology, although I was a chemist by training. In fact, there's only, I think, two bonafide chemists with PhDs in the room, John Martin and myself, [00:03:30] but we worked initially on several drugs, which I'm going to talk about today.

Really, other than d4T, these are truly novel molecules. They're not repurposed drugs from the cancer world, like AZT was. These are completely novel molecules, a bit like nevirapine, for example. Of course, we're going to hear from Daria [Hazuda] and others on integrase inhibitors. These were totally novel compounds that really had tremendous impact on the field of HIV as well as [00:04:00] other viruses. These are the five drugs I have personally been involved with from the beginning (d4T, LdT, FTC 3TC, and sofosbuvir). I list them there and the collaborations among the universities, the drug companies, as well as the patients that took these drugs and allowed us to get beautiful data to demonstrate that these drugs are effective and safe in patients. Most of them are safe at least.

Raymond F. Schinazi (b. 1950) is a medical chemist and virologist at Emory University School of Medicine who co-developed the anti-HIV drugs d4T and 3TC.


Jump to:


I want to go through some of the stories. I think you do know that FTC, [00:04:30] as well as the other nucleosides that you heard about today from Sam Broder and others, these compounds are phosphorylated to the triphosphate form and these incorporate as chain terminator. There are many ways they can incorporate as chain terminator, I'm not going to talk too much about biochemistry, but it really requires a team to discover and characterize nucleoside antiviral agents.

You don't just go and call Aldrich Chemical or Sigma and ask for these compounds. There's a lot of work that goes into [00:05:00] the design, the chemistry, the biology, the computational work, the modeling, the biochemical pharmacology, the antiviral testing using robust systems, like we heard today from Marty St. Clair, and the antiviral characterization in terms of resistant virus as we heard from Doug Richamn and, of course, animal work and pre-clinical-- eventually you get lead compounds from many hits that you have. It's a lot of work. I'm not going to go through how to discover compounds, but it is important to have the proper properties.

# drug safety

A good drug [00:05:30] will generally possess these attributes, basically absorption, distribution, metabolism, and excretion. These are all important things. You don't want these drugs to work just once. Basically, that they have eventually—When you stop treatment, you either get the patient healed and the drug basically clears the body. You don't want it to accumulate in organs forever. You want it, ideally, to be orally or injection [00:06:00] or whatever you decide. These are important points, and you don't want too much metabolism, the drug breaks down and clears the body too quickly before it reaches the target. These are things that we do.

I learned a lot of my virology—I was working with Bill Prusoff at the time. Then, when I left the lab, I set up the first HIV lab at Emory. Interestingly, in those days, CDC didn't have a barrier. [00:06:30] You could walk across CDC and you could go up to the BL4 (biosafety level 4) facility, and you can actually pick up a vial of HIV and take it back to Emory without any paperwork. Quite amazing in those days. Of course, today, you can't even—They check your car, they check your hood, they check your passport. You cannot go in and it's incredible.

There was this spirit, an incredible spirit of cooperation because we knew we had a major disaster on our hand. People were willing to collaborate and give us the virus. Of course, I took this virus [00:07:00] shaking my hands. My wife, at the time, wouldn't even talk to me for several months, but that's another story.

[laughter]

Basically, the first drug, we had a very robust. We decided very early on, and thank goodness it turned out to be a virus and not some other organism, because I was trained for that and actually I had AZT in our lab at the time. Probably one of the only labs in the country, because I had been working with Bill Prusoff, we had made AIU, another compound that didn't make it to the clinic, but [00:07:30] it actually was very useful because it proved that the viral TK (thymidine kinase) was very important and you could actually target the virus and not the host. That led to the discovery of aciclovir, of course.

Also, the same principle could be used for nucleosides like d4T, they are basically better substrates for the viral polymerase than the natural polymerase, so that's again why we have this advantage. D4T is not the ideal drug, but at that time it served it's purpose. You can [00:08:00] see the structure on the left-hand side. This was worked on by Tai-Shun Lin, a chemist in the lab who worked on the other bench when I was at Yale University. Dr. Prusoff and we worked on this compound. It was sent to me actually blind, to be honest, in my lab because we had a very robust PBMC system. I tested it and I immediately called Bill. I said, "Bill, we got something really hot here. I've never seen anything so potent against HIV."

I was doing the assays myself [00:08:30] in those days. I don't have the team I have today. We're very excited and we quickly put out this rapid communication in Biochemical Pharmacology. (1) In the paper, we talked about a DDDT and I got sick of saying DDDT, it sounded like DDT, so I decided to call it d4T and that's how the name came through. What's amazing about this compound is that even today, or at least three years ago, I should say, over a million individuals still take this drug [00:09:00] despite its problems.

#ADME (absorption, distribution, metabolism, excretion)

#lab safety, biosafety levels, safety protocol

It's not the greatest drug in the world, but it served its purpose, the same way as AZT served its purpose at the time. It was a thymidine kinase-dependent drug like AZT. At the time, that was an important drug when it first came out, and many combination studies were done with d4T. Of course, combining AZT with d4T was not a good idea because they both use the same enzyme, if you remember work done by several [00:09:30] people in clinical trials. It failed in the lab and it also failed in the clinic.

The real revolution really took place when we discovered, what we call today, the L-nucleosides. These are basically mirror images of compounds. You have your left hand and your right hand. They are not superimposable. You also have shells, for example. You can see a shell there, mirror images of shells. 

[00:10:00] They're not mirror images, actually. You can find shells growing one way or the other. Maybe on a different planet, it will grow differently, but on this planet, that's the way they are. It's very interesting how the structure occurs for the shells. I'm not a chonchologist, but this is something that can be studied by other people other than myself, but basically we had mirror images of compounds.

We understood very quickly that these compounds could be phosphorylated, and both the D and the L isomer, the D being the natural one and the [00:10:30] L being what they called unnatural—but really, it's not that unnatural because if you look at the literature, a paper I published many years ago with a postdoctoral fellow, it was actually a review article looking at L-nucleosides. (2) We had found that L-adenosine actually is a natural compound, so there was in nature L-nucleoside. It's not something totally foreign to this planet. Maybe on another planet it's all L, [00:11:00] but here plants use it as a chemotactic agent.

In fact, Dr. Holý—We'll hear more about Antonín Holý, the great scientist from the Czech Republic, actually worked on the synthesis of L-adenosine and he actually published the paper on the synthesis of how to make L-nucleosides. (3) Itwas actually fundamental work on how to do this work led I believe strongly to the discovery of 3TC and FTC later on. 00:11:30] He's being remembered specifically for his work on tenofovir and other drugs, but I think his early work contributed to the discovery of 3TC and FTC.

 

 

#lab vs. clinic

 

#chirality

 

In 1986, I went to England to see my old mentor at the Bath University. I told him, "Can we make a dioxalane? Can we synthesize oxathiolane? He said to me, "It's impossible. You're wasting your time." "Why is it impossible?" He said, "While you have a carbon with two [00:12:00] oxygens attached to it or oxygen and sulfur, and that's not going to be stable." Historically, if we look at this, basically everybody shied away from making these type of compounds because they felt they were impossible to synthesize. If you ask any chemist back in 1986, '87, '88, even '89, they will say, "You're crazy. Don't waste your time. It's not going to be funded. If you're writing an NIH grant, you'll definitely not get funded" because they'd say it's impossible to make these types of compounds.

These oxathiolanes [00:12:30] were actually used as protecting agents. We knew that under acidic condition, they are easily cleaved and you open up the ring. What people didn't realize is that you have a cyclic system and this cyclic system produces a unfavorable molecule that you can see there in the bottom middle that is not favorable chemically. Basically, the ring goes back—the reaction goes back to the left-hand side instead of [00:13:00] moving forward to the right-hand side and opening it up. 

We thought it was impossible and even I thought it was impossible until I went to Montreal and I saw a beautiful paper presented by Dr. Bernard Belleau (1925–1989) and colleagues in Canada, who actually had made dioxalanes and had made BCH-189, which at the time was a 50/50 mixture that nobody seemed to know how to separate.

Eventually, this compound was tested in culture by Mark Wainberg. His picture is shown there, [00:13:30] a nice picture of Mark Wainberg on the bottom. He published a short paper showing that BCH-189 was active. (4) That actually was a racemic mixture of BCH-189, but the big puzzle was how to make this compound and what isomer is really the active form of the molecule, because there's two possible isomers, there's the plus isomer and the minus—Sorry, the plus enantiomer and the minus enantiomer. There's also actually two other forms, the trans versus [00:14:00] the cis, of the nucleosides.

Working with Dennis Liotta at Emory and Woo-Baeg Choi, we made actually all the four isomers of BCH-189. Although Belleau had actually made the racemic mixture, we actually made all the isomers and we demonstrated for the first time that the minus enantiomer was not toxic. Actually, it was very interesting. The plus is toxic, especially in CM cells (memory T cells), but not many other cells. Bone marrow toxicity [00:14:30] was quite high with the plus enantiomer but not with the minus. That was really the beginning. We published that in Antimicrobial Agents and Chemotherapy. (5) With that discovery—so we discovered that there was a less toxic form and also people at Glaxo at the time who had licensed the drug from BioChem Pharma also demonstrated similar results, that the unnatural enantiomer had a much-improved profile, at least in cell culture.

What [00:15:00] was important, and we mentioned that earlier, is process chemistry. Everybody can make a beautiful compound and you can make maybe three milligrams in the lab, but now you have to scale it up, so you need process chemistry and you need process chemists. We were not processed chemists, but we pretended to be process chemists, Dennis and myself, and we decided to develop a process for making BCH-189 to resolve the enantiomers which allowed to do the previous experiments.

What I can tell you is that we were successful. We actually licensed our process to Glaxo, [00:15:30] and they made four tons of BCH-189 using our chemistry that was developed at Emory University. That allowed them to proceed with a clinical trial, so we probably cut down—Remember, they would have four possible isomers when you make this compound and they would have to throw three of them to get the right one and separate the one. That was really a coup de grace, that a relatively small university could actually compete with a big pharma at the time. [00:16:00] 3TC, as you know and we'll hear more about that, was now used for many drug combinations. Combivir (AZT+3TC), of course, was the first one, Epzicom (ABC+3TC) and Trizivir (ABC+3TC+AZT).

I'd like just to divert for one minute, if I may, on the story of 3TC and AZT. When the trials on 3TC were being carried out all over the world, one patient intentionally [00:16:30] took AZT in combination with 3TC. We actually presented that at the national meeting, demonstrating for the first time that the combination. [unintelligible 00:16:40] was doing monotherapy, as you may remember, and of course 3TC fairly rapidly develops resistant virus, so that's a problem, but this patient was smart enough, smarter than some of the clinicians in actually using AZT that he had leftover from a previous study and added it to 3TC. I can tell you my poster, it was a poster presentation, [00:17:00] was mobbed by the drug companies and many people, because this was actually the very first time somebody had used a combination chemotherapy and we had found out about it. That's just a side story, which I think is interesting.

Let me just move. Let's talk about chemistry. I know you're not all chemists, but I'm going to try and explain it to you because I think it's very important to understand how serendipity really plays a role sometimes and luck—I'll take luck whenever I can. [00:17:30] A lot of the chemistry was developed by Dennis and myself with a postdoctoral fellow, probably the luckiest postdoctoral fellow. He (Woo-Baeg Choi) was a Korean scientist in Dennis's lab. We worked together trying to come up with a synthetic process for making the compound.

This work actually was published in JACS. (5, 6, 7) You probably don't even know what JACS is, Journal of American Chemical Society. It's the Science paper for chemists. That's where they go to publish their most important work. [00:18:00] They don't go to Science to show this. They show how brilliant they are in chemistry. We weren't that brilliant, actually—We weren't that brilliant, but we came upon this process by accident because a young scientist didn't understand that the value of Lewis acids, which are critical for the coupling reaction between the sugar part, the sugar moiety and the base. He didn't have any reagents, but he came to my lab and picked up stannic chloride, which I happened to have on my shelf, and used [00:18:30] stannic chloride and, lo and behold, much to his surprise, he had 200:1 excess of the right enantiomers. That's pure luck.

We couldn't explain it why. Initially we couldn't explain it, but of course we sounded brilliantly in the paper how we did it. We resolved this, we hypothesized that the stannic chloride binds to the sulfur and forces the base to come from the top and that's how the drug works. This was really a breakthrough that allowed us to make large quantities of these molecules. Not only these [00:19:00] molecules, but many other analogs. It didn't take long to make analogs of these compounds.

Then, after that, we made basically a prodrug of this racemic BCH-189. Using enzymology, were able to separate the two enantiomers because one enantiomer would be—There was another way of doing it too, by the way, using deoxycytidine deaminase. Deoxycytidine deaminase basically [00:19:30] reduces the amino group to an oxygen and you make the O—instead of making the cytidine analog, you're making uridine analog. The uridine analog is not active, but you can separate very easily the cytidine analog from the uridine analog. That was key.

I'm sorry for boring you with all the chemistry, but I think I wanted to tell you sometimes luck does happen. Of course, the story of FTC (emtricitabine) is very complicated because 3TC was way ahead, almost approved, and we were still pushing FTC. People told us [00:20:00] that FTC would never work because it would get cleaved, you would form 5-FU, 5-FU would be toxic. Again, science came to bear and science proved to us that the cleavage reaction everybody thought would happen did not happen with FTC and the drug was very stable. In fact, we well know about it now. The drug came from Emory to Burroughs Wellcome back to Emory back to Triangle [Pharmaceuticals] and eventually ended up with Gilead. That's the path, a very complicated path.

[00:20:30] There's been talk about, "Are they equal-- these two drugs are equal? Are they equipotent?" All this stuff, discussion. It doesn't really matter. I think the bottom line is we know that the triphosphate level in the FTC is about 10 times more potent than the 3TC at the enzyme level, but really it doesn't matter too much. It may matter in terms of resistance, probably that fluorine adds a bit more hydrogen bond and that's probably why the compound works the way it does.

 

 

 

#funding and grants

One of the major surprises to us, I know it's obvious now, the [00:21:00] M184 mutation, which at the time I called "The mother of all mutations," the active site of HIV, was discovered in our lab with collaboration with John Mellors because I couldn't believe my data, so I sent some powder to John and said, "Please repeat my work and see if you can get it." Lo and behold, he was able to select a virus with the M184 mutation.

We now understand better why this occurs and we understand the clash that occurs in [00:21:30] the polymerase when you have a sulfur ring versus an oxygen or versus a CH2 group, and that led to the mutation, which is well known. It wasn't just a few-fold increased resistance, but over a thousandfold, independent on assay you use. That was a fundamentally important discovery because that also led to the idea of combination chemotherapy. We have one single mutation being selected, if we hammer it with another drug, possibly that could be a wonderful combination.

One of the side effects of [00:22:00] working with these drugs was that we thought, "These compounds work against the polymerase. Why can't we test them against HBV (hepatitis B virus)?" At the time, there was not many people in the country who could actually test for hepatitis B activity in vitro. We send some of the powder to Tommy Cheng (Yung-Chi) at Yale and he was able to confirm that these compounds, both FTC and 3TC, were active against hepatitis B. That actually became, as you know—3TC became [00:22:30] the first orally available hepatitis B drug. I should give credit also to the people at Burroughs Wellcome.

#reproducibility; experimental reproduction

 

This is Cheng's paper on PNAS. (8) And Burroughs Wellcome scientists also discovered the activity of 3TC and FTC with the Emory group, and published almost within a few months from each other. (9) That was really important because we had a compound now that had dual activity against HIV as well as HBV for the first time, which was very, very exciting. [00:23:00] 

Another compound that came from my work as well as the work of Dr. [Jean-Pierre] Sommadossi at UAB (University of Alabama at Birmingham) and, eventually, a company that we co-founded, Idenix Pharmaceuticals, was telbivudine. This compound is not even an analog, it's just thymidine, it is the L-isomer of thymidine, so you can't even call it an analog. And this compound is approved for treatment of hepatitis B today as an oral drug, and is used widely in China. Unfortunately, it has the same profile as 3TC and FTC. But [00:23:30] it is a B-class molecule and it can be used in pregnant women. That's one of the advantages. That was one of the nice dividends of working on these L-nucleosides.

I'm sure you know all the story of Sovaldi (sofosbuvir). That's not an L-nucleoside, it's a beta-D analog with the story of hepatitis C polymerase. This was also an amazing experience of working on nucleosides. We knew that there is no latency with HIV. Therefore, we could develop nucleosides that could work [00:24:00] selectively. The first compound we worked on was a compound called PSI-6130. That compound became mericitabine. Of course, subsequently, we discovered that PSI-6130 monophosphate is deaminated to the U-analog, and the U-analog, the triphosphate form, is active against hepatitis C virus.

That was quite [00:24:30] exciting because it led to the modification and ability to deliver the U-analog intracellularly using a phosphate prodrug. I think that was using a [Chris] McGuigan (1958–2016) type of chemistry, but the warhead was actually discovered earlier by a group—a young bachelor, I think he has a master's degree, Jeremy Clark, a chemist in my group, who made the [00:25:00] first couple of milligrams of the compound.  (10) Subsequently, we had to make large quantities of these compounds.

I can tell you the cost. We talked about making compounds, it costs us almost a million dollars a kilo of 6130 to make at the time. It was a very high risk proposition. We actually had to make three kilos of this compound. It wasn't easy. The process chemistry of making this compound is not easy. Fortunately, now, they can make it in very large quantities because it has [00:25:30] fluorine and a methyl group at the two prime position and, of course, the prodrug now with a phosphate prodrug that becomes the drug, phosphate as a curative therapy for hepatitis C virus, which is very, very exciting.

Looking ahead, and I'm almost finished, nucleosides are the first-line agents for emerging viruses and also—This is something that we looked at. In fact, we've seen it happen recently with the Ebola outbreak, that John is going to talk about it, but [00:26:00] one of our HCV (hepatitis C virus) compounds that didn't make it was repurposed for the treatment of Ebola virus and it seems to be quite potent. Unfortunately, it will come back—the virus will come back and we'll be able to use it again in larger number of people.

Certainly, nucleosides are becoming quite exciting for West Nile virus, dengue virus, Zika virus and, of course, we shouldn't forget HIV. There's still hope for additional nucleosides and we'll hear more maybe from Daria [Hazuda] on EFdA (islatravir), [00:26:30] a wonderful drug that has tremendous potency. I think the ultimate goal is to develop a broadly active nucleoside analog that will work against all viruses and we're beginning to work on that in our lab.

#simultaneous discovery (multiple discovery)

We talked today about inflammation and immune modulators. We're also working in this area in terms of so-called cure. Of course, the ultimate goal, having been so successful with hepatitis B with the nucleosides that are currently available, [00:27:00] it's time to develop other compounds like capsid inhibitors. We have very potent compounds in this class of compounds. We hope to combine them with NUCs and get very powerful effect and maybe even have an effect on cccDNA, which could be quite exciting. This is where we are.

Now, the big present of all this work, the real present is not—the big reward we've had is really saving lives, which is something we all [00:27:30] try to do. We've seen some horrible pictures today of patients with blisters, with redness, with conjunctivitis, severe conjunctivitis I mean. But to think that this small molecule, these small pills can actually make a difference and save and control and even cure some patients, that to me is very gratifying.

I can tell you that more than 94%, if not more, of the treated HIV-infected persons today take a [00:28:00] nucleoside analog. The story started with AZT, but it's not finished. There are many more drugs to come in terms of nucleoside analog in the future, not just for HIV and HBV and Ebola, but many other emerging viruses. I'd like to just end by first thank the NIH for their support for many years, the Department of Veterans Affairs for almost 35 years of funding and, of course, my group which is composed of a lot of biologists, but also [00:28:30] the ones in blue are all chemists.

It's important to recognize the chemists who actually make these molecules, very creative chemists in my lab and other people's lab who bring out these amazing molecules that have tremendous impact. I know the glory is in the biology, but certainly the chemists should also get some praise. We want to thank the patients who participate, as I mentioned earlier, but also I think, very important, we shouldn't discount [00:29:00] the private/public sectors for assisting the academic enterprise.

I'm still a professor at Emory University. People think I work for companies. I never worked for a company. I'm always—working still at Emory University and I'll probably remain there until my last breath. Basically, this is where action is taking place. We can discover drugs in university settings, we can be very successful. That hopefully gives hope to some of the young people in the audience. Thank you very much.

[applause] [00:29:30] 

Eddy Arnold: I have a question. Polymerases are just fantastic targets, of course, reverse transcriptase is the central drug target for HIV, but sofosbuvir it's such a knock-it-out-of-the-park drug. Given the incredibly high viral loads that you have with HCV, [00:30:00] how does it work so incredibly well?

Ray: I think first you have to have the warhead and then you have to have the delivery system. I think the genius is both in the warhead and the delivery system. Delivery system was actually discovered, which actually was used for sofosbuvir, fortunately, by [Chris] McGuigan who died recently, as you may know, in Glasgow, a great chemist also in England—in the UK. At least, Wales is still [00:30:30] part of England, so we'll see what happens.

Anyway, I think this was the key because the drug itself—There are several points. First, the drug is absorbed through the intestine intact, gets to the liver, so it targets the liver. It actually breaks down primarily in the liver, so you have a high concentration of the monophosphate form, what we used to call [00:31:00] PSI-6206, which is the uridine analog monophosphate, the monophosphate of 61—6206, sorry. That compound is actually the active form in that it is phosphorylatedto the triphosphate form. Interestingly, if it was to break down back to the U-analog, that was the 6206 go back to the nucleoside, [00:31:30] from monophosphate to the nucleosides with alkaline phosphatase or whatever enzyme or phosphodiesterase, the actual molecule is innocuous, it's not active. It is totally inert. That's what makes it so specific.

It's pretty unique. You actually take a drug that is totally inactive, you make a prodrug and it's active. Not only is it active, but it has a longer half-life than the C-analog [00:32:00] triphosphate. Intracellular half-life you can give once a day, as you well know. That's why the drug is so powerful, I think. You can concentrate it. Unfortunately, it can't go very high. People don't know that, but if you take sofosbuvir in culture to very high levels, 15 micromolar or more, you start seeing mitochondrial toxicity and other problems. I'm not going to spend my time on my life figuring out why, but clearly it does have toxicity at high level. You can't really push the dose. The dose today is 400 milligrams, [00:32:30] maybe other people can speak to it, but I don't think you can-- at least for prolonged period of time, you cannot jack up the dose to say 800 or 1,600 milligrams a day. That's the problem with this drug.

Eddy: Why is there no resistance?

Ray: That was actually work done by Daria Hazuda and her group. Her group demonstrated that—published even before the discovery. They were playing like Larder did with HIV, making site-directed [00:33:00] mutants seeing what's going to work, what's not going to work, whether resistance is going to occur. Typical virologists doing site-directed mutagenesis. They were able clearly to demonstrate that the virus is highly debilitated so that you can't get resistance.

The key mutation for these nucleosides is S282T, changed it from S to T. That was the fingerprint for this particular class of nucleosides. There are other mutations, but this was the primary one [00:33:30] and the virus is heavily debilitated. It can happen, but it doesn't persist, it doesn't stay. A bit like the M184V in HIV, comes and goes, it doesn't stay forever. Maybe stays in the reservoir. That's a different story.

Sandra Lehrman (moderator): Great. Thank you.

[00:33:48] [END OF AUDIO]


#cure vs. remission of HIV/AIDS

Citations

  1. Tai-Shun, Lin, Raymond F. Schinazi, and William H. Prusoff. “Potent and Selective in Vitro Activity of 3’ -Deoxythymidin-2’-Ene (3’-Deoxy-2’,3’-Didehydrothymidine) against Human Immunodeficiency Virus.” Biochemical Pharmacology 36, no. 17 (September 1, 1987): 2713–18. doi:10.1016/0006-2952(87)90253-X.
  2. Graciet, Jean-Christophe G., and Raymond F. Schinazi. “From D-to l-Nucleoside Analogs as Antiviral Agents.” In Advances in Antiviral Drug Design, edited by E. De Clercq, 3:1–68. Elsevier, 1999. doi:10.1016/S1075-8593(99)80003-3.
  3. Jurovčík, M., and Antonín Holý. “Metabolism of Pyrimidine L-Nucleosides.” Nucleic Acids Research 3, no. 8 (August 1976): 2143–54. doi:10.1093/nar/3.8.2143.
  4. Soudeyns, Hugo, Xiao-Jian Yao, Qing Gao, Bernard Belleau, Jean-Louis Kraus, Nghe Nguyen-Ba, Bonnie Spira, and Mark A. Wainberg. “Anti-Human Immunodeficiency Virus Type 1 Activity and in Vitro Toxicity of 2’-Deoxy-3’-Thiacytidine (BCH-189), a Novel Heterocyclic Nucleoside Analog.” Antimicrobial Agents and Chemotherapy35, no. 7 (July 1991): 1386–90. doi:10.1128/AAC.35.7.1386.
  5. Schinazi, Raymond F., Chung K. Chu, Annette Peck, Angela McMillan, Rodney Mathis, Deborah Cannon, Lak-Shin Jeong, et al. “Activities of the Four Optical Isomers of 2’,3’-Dideoxy-3’-Thiacytidine (BCH-189) against Human Immunodeficiency Virus Type 1 in Human Lymphocytes.” Antimicrobial Agents and Chemotherapy 36, no. 3 (March 1, 1992): 672–76. doi:10.1128/AAC.36.3.672.
  6. Choi, Woo-Baeg, Lawrence J. Wilson, Suresh Yeola, Dennis C. Liotta, and Raymond F. Schinazi. “In Situ Complexation Directs the Stereochemistry of N-Glycosylation in the Synthesis of Thialanyl and Dioxolanyl Nucleoside Analogs.” Journal of the American Chemical Society 113, no. 24 (November 1991): 9377–79. doi:10.1021/ja00024a058.
  7. Schinazi, Raymond F., Angela McMillan, Deborah Cannon, Rodney Mathis, Robert M. Lloyd, Annette Peck, Jean-Pierre Sommadossi, et al. “Selective Inhibition of Human Immunodeficiency Viruses by Racemates and Enantiomers of Cis-5-Fluoro-1-[2-(Hydroxymethyl)-1,3-Oxathiolan-5-Yl]Cytosine.” Antimicrobial Agents and Chemotherapy 36, no. 11 (November 1, 1992): 2423–31. doi:10.1128/AAC.36.11.2423.
  8. Doong, Shin-Lian, Ching-Hwa Tsai, Raymond F. Schinazi, Dennis C. Liotta, and Yung-Chi Cheng. “Inhibition of the Replication of Hepatitis B Virus in Vitro by 2’,3’-Dideoxy-3’-Thiacytidine and Related Analogues.” Proceedings of the National Academy of Sciences 88, no. 19 (October 1, 1991): 8495–99. doi:10.1073/pnas.88.19.8495.
  9. Furman, Phillip A., Michelle Davis, Dennis C. Liotta, Melanie Paff, Lloyd W. Frick, Donald J. Nelson, Ronna E. Dornsife, et al. “The Anti-Hepatitis B Virus Activities, Cytotoxicities, and Anabolic Profiles of the (-) and (+) Enantiomers of Cis-5-Fluoro-1-[2-(Hydroxymethyl)-1,3-Oxathiolan-5-Yl]Cytosine.” Antimicrobial Agents and Chemotherapy 36, no. 12 (December 1, 1992): 2686–92. doi:10.1128/AAC.36.12.2686.
  10. Clark, Jeremy L., Laurent Hollecker, J. Christian Mason, Lieven J. Stuyver, Phillip M. Tharnish, Stefania Lostia, Tamara R. McBrayer, et al. “Design, Synthesis, and Antiviral Activity of 2‘-Deoxy-2‘-Fluoro-2‘-C-Methylcytidine, a Potent Inhibitor of Hepatitis C Virus Replication.” Journal of Medicinal Chemistry 48, no. 17 (August 1, 2005): 5504–8. doi:10.1021/jm0502788.

 

Index 

 

 

Found 6 search result(s) for Schinazi.

Page: Science (journal) (HIV/AIDS Research: Its History & Future Meeting)
... St. Clair: Discovery of AZT as the First AntiHIV Drug https://libwiki.cshl.edu/confluence/display/AT/3.1MartySt.Clair%3ADiscoveryofAZTastheFirstAntiHIVDrug 3.4 Raymond Schinazi — Discovery and Development of Novel NRTIs https://libwiki.cshl.edu/confluence/pages/viewpage.action?pageId=12943501 4.1 Ronald Desrosiers — The Origin of SIVmac ...
Mar 06, 2021
Page: 3.6 John C. Martin — Making it Simpler: A Single Pill to Treat HIV (HIV/AIDS Research: Its History & Future Meeting)
... see Erik De Clercq, Tony Holý, and Bill Prusoff, who Raymond Schinazi talked about. Raymond collaborated with Bill on d4T, I collaborated with Bill on d4T ...
Apr 27, 2021
Page: 3.5 Daria Hazuda: Discovery and Development of Integrase Inhibitors (HIV/AIDS Research: Its History & Future Meeting)
... here and it was just not nonspecific chelation. I give a lot of credit, just as Raymond Schinazi did, to people who I think are among the many unsung heroes in this field ...
Apr 27, 2021
Page: 3.2 Samuel Broder: The First Clinical Trials of Antiretroviral Drugs (HIV/AIDS Research: Its History & Future Meeting)
... d4T (stavudine, Zerit), which 00:23:30 originated from Ray Schinazi and others, it was not approved until seven years later, and the sponsor was a BristolMyers Squibb. 3TC ...
Apr 27, 2021
Page: 4.1 Ronald Desrosiers — The Origin of SIVmac: Non-human Primate Models for HIV (HIV/AIDS Research: Its History & Future Meeting)
... out ways to try to tease the immune system there, but this approach circumvents the problems. Raymond Schinazi: Very exciting results that you have at the end. I wanted to know how ...
Apr 27, 2021
Page: 2.4 Robert Gallo — Discoveries of Human Retrovirus, Their Linkage to Disease as Causative Agents & Preparation for the Future (HIV/AIDS Research: Its History & Future Meeting)
... drugs, and I refer you to the talks of Sam Broder, John Martin, and Ray Schinazi. When therapy became available, we could determine who to treat as well ...
Apr 27, 2021


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