New Class of Drugs to Block SARS Being Developed at UIC

UIC Podcast
UIC Podcast
New Class of Drugs to Block SARS Being Developed at UIC
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News Release

 

[Writer] This is research news from U-I-C – the University of Illinois at Chicago.

Today, Andrew Mesecar, professor of pharmaceutical biotechnology, talks about how UIC researchers are developing a new class of drugs to block the spread of the virus that causes Severe Acute Respiratory Syndrome, or SARS.

Here’s professor Mesecar:

[Mesecar] We have an ongoing project in my laboratory, which is to search for drugs that would combat the SARS (severe acute respiratory syndrome) virus, should it ever return here on the plant.

Back in 2002, there was an outbreak of SARS in late December which caused over 10,000 infections worldwide. This was the first pandemic of the 21st Century and essentially set up a framework for the world in terms of how are we going to combat any emerging infectious diseases over the next century.

Shortly after the outbreak, where over 10,000 people were infected, over 10 percent of those people died. And the question was, how are we going to rapidly develop therapetics?

The National Institutes of Health put out a number of RFAs (requests for applications) for investigators in the United States to develop vaccines and small-molecule therapeutics.

We jumped in and wanted to make a contribution and set up a program project to search for small-molecule therapeutics that would work against the SARS virus.

Our approach was based on the success of the HIV protease inhibitors, which were developed over the course of a decade, starting in the 1990s. We teamed-up with a group from Purdue University – Arun Ghosh, who was originally here at UIC who has an HIV protease inhibitor called darunavir, which was put on the market in 2007. So he was a perfect person to help in this endeavor. We also teamed-up with a coronaviral expert named Susan Baker at Loyola University (of Chicago) to handle the virology project. My role and my lab’s role in the project was to discover the molecules initially that would lead to the development of the therapeutics.

So our approach stemmed from the protease inhibitors from HIV. We looked at the SARS virus and noted that there were two proteases that we could potentially target: one called the chymotrypsin-like protease, the other called the papain-like protease.

The 3 chymotrypsin-like protease was actually developing other viruses that cause the cold, such as the picornavirus. So we thought it has a lot of therapeutic potential. But the papain-like protease was a protease that was never ever researched in terms of whether or not we could target this with drugs. So we went with the idea that because this protease is essential, that maybe we could find small molecule compounds that could inhibit that particular protease and therefore stop viral replication.

The challenge that we had to overcome is the fact that there were no known small molecule compounds in the world that inhibited this particular protease.

So it becomes a needle in a haystack problem. First thing we had to do was get a haystack. To get the haystack, we accumulated over 100,000 chemical compounds that were purchased from a variety of different vendors worldwide. We had to store, barcode these compounds, understand their structures and all of the associated pros and cons of the chemistry.

Once we had this all together, then we were faced with the challenge of having to screen these compounds against the papain-like protease.

To do that, we brought on our robotics systems – liquid-handling robotics. Sort of a small version from what the pharmaceutical industry is doing and how they screen their haystacks for these needles, which serve as a lead compound, what we call a drug compound. And once we had all of this technology in place, then it was a matter of getting down to it and screening.

Over two weeks of research and effort time between my graduate student Kiira Ratia and Dr. Scott Pagan in my lab, continually went through plate after plate of these compounds, and out of 50,000 that they screened through, they arrived at 40 compounds that we thought may have potential.

After looking at the compounds, trying to understand whether or not they could be drugs or would they be toxic, we went through a number of different assays to test whether or not these compounds would be good or bad.

So after arriving at two of these compounds – two out of 50,000 – we were at the point where, “well, now what do we do?”

This is where out collaborator Arun Ghosh came in, looked at the compounds and said these have a lot of potential, but we need to make them more potent.

So with his group of synthetic chemists, they continued to improve the potency of these compounds such that they stuck to the enzyme pretty much like Velcro – basically slamming right down into the site and then sticking.

But what was important at this point is these compounds that we found and that the Ghosh lab improved upon were not too potent, in terms of their strength of interaction. In other words, there’s something called a reversible inhibitor – a reversible drug. So the reason why this was so important was that the molecules didn’t covalently act like a warhead and knock out this enzyme. This enzyme is something called the cysteine protease – no therapeutic drugs have been put on the market that target cysteine proteases. And the reason is all of the compounds that have been developed by the pharmaceutical industry have these warheads – something that completely knocks out the enzyme by these active site cysteines.

The problem is, this amino acid, this cysteine residue, is in every protein in a cell. And if you have something that non-specfically warheads and takes them out like a bomb, then you’re going to have a lot of toxicity. So we were able to develop a non- covalent, non-warhead containing compound that was able to hit this site.

Most importantly was the fact that these compounds have anti-viral activity in cell culture and they have no associated toxicity. So it gives us the groundwork now to increase the potency of these compounds and to increase their therapeutic potential so that we can do animal studies, which we’re preparing to do shortly. If those should pan out, and we have no toxicity in animals, then we’ll ramp-up and begin to get through the therapeutic development pipeline.

Now the importance now of moving forward in the animal studies is that they don’t have any associated toxicity in animals, it will lay the groundwork for further development in looking for a partner company or entity that would help us continue on the development.

[Writer] Andrew Mesecar is a professor of pharmaceutical biotechnology.

For more information about this research, go to www-dot-news-dot- uic-dot-edu (www.news.uic.edu) … click on “news releases.” … and look for the release dated November 13, 2008

This has been research news from U-I-C – the University of Illinois at Chicago.

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