Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

"The beauty and mystery of life
extends down to the molecular level. 

The more we see, the more we can appreciate
the wonder of our own nature."

Prof Arthur Olson, Scripps Institute



Every now and then, something lands in my Google Reader that makes me stop and gasp, or at least eagerly look a little more closely. Today's head turner was:

"Scripps Research scientists find two compounds that lay the foundation for a new class of AIDS drug"


Whoa!
On more
careful examination, it seems that a team of scientists at The Scripps Research Institute really has identified two compounds that act on novel binding sites for an enzyme used by the human immunodeficiency virus (HIV), the virus that causes AIDS. The discovery apparently lays the foundation for the development of a new class of anti-HIV drugs to enhance existing therapies, treat drug-resistant strains of the disease, and slow the evolution of drug resistance in the virus.

I've written about AIDS and HIV previously and how the disease evades treatment in the past, but if this new finding holds true, we could potentially have a new approach that will add to the current pool of treatment regimens that slow down the path to drug resistance and improve patient outcomes.

Current HIV-protease drugs mimic the shape of certain regions of the HIV protein chain, known as the "cleavage sites" and bind to the active site in the hollow center of protease.  Once this site is blocked by the drug, the protease is disabled, and HIV cannot make new infectious particles.  Protease drugs therefore impede the spread of the HIV infection to other cells within a patient.

The researchers decided to look at drug-resistant strains of the virus.  They then conducted computer simulations of the movement of a particularly nasty multi-drug-resistant mutant strain of HIV (V82F/I84V) to see what happened and if they could learn from it.

The results showed that the flaps of the drug-resistant protease molecule tended to be open more often than their counterparts and they were also more flexible. While the anti-HIV drugs still fit into the active site binding pocket, more energy was needed to close the flaps than the drugs could muster.  The drugs wouldn't stay in the binding site and the pocket remained available for the HIV protein chain, which was still able to close the flaps and go on to create new infectious particles.

We can now see that a new type of drug might be able to bind to alternate sites on the sides of the protease, restraining the flaps from their ends and providing the current anti-HIV drugs enough help to close the flaps and disable the protease. Instead of blocking the protease's active site, these compounds would be "allosteric fragments" ie small molecule building blocks that shift the dynamics of the molecule, allowing a different conformation or shape.

How are these two compounds different from currently approved drugs for HIV?

Well, in plain English, current treatments target HIV protease, however, the two new agents in development are small chemical units or "fragments," which bind with the two specific parts of the molecule where they identified resistance occurring.

Essentially, this approach is an important proof-of-concept that the protease molecule has two non-active site binding pockets or 'allosteric sites', which can be exploited as a powerful new strategy to combat drug-resistance in HIV.

Overall, there is a long way to go yet, including extensive clinical trials to determine the safety and efficacy of the compounds, but in theory, with this approach, future drugs incorporating the fragments' novel structural elements may offer new angles that can be exploited biochemically.

Take a look at a beautiful picture of the HIV complex, courtesy of the Scripps Institute, which was created by Dr Stefano Forli, Ph.D:

Forli_HIVreflection
Once you have finished comtemplating, please re-read the quote at the top of the post. The more we understand about the science and biology of disease, the more awed I feel.

You can also check out the Scripps Fight AIDS at Home page if you want to learn more.


ResearchBlogging.org
Perryman, A., Zhang, Q., Soutter, H., Rosenfeld, R., McRee, D., Olson, A., Elder, J., & David Stout, C. (2010). Fragment-Based Screen against HIV Protease Chemical Biology & Drug Design, 75 (3), 257-268 DOI: 10.1111/j.1747-0285.2009.00943.x

3 Responses to “Novel therapies could improve potency of existing AIDS treatments”

  1. Alex L. Perryman, Ph.D.

    Dear Dr. Sally Church,
    I need to correct a few things:
    “current treatments target HIV protease, however, the two new agents in development are small chemical units or “fragments,” which bind with the two specific parts of the molecule where they identified resistance occurring.”
    Most of the drug resistance mutations are found within the active site, in the hollow center of the enzyme. These fragments bind to two different regions of protese (i.e., not the active site). When these allosteric fragments bind to HIV protease, they stabilize the inhibited, drug-bound conformation of protease, which has closed flaps. The mechanism of resistance for several multi-drug-resistant mutants seems to involve the protease displaying more flap opening behavior and greater flap flexibility. Thus, these fragments don’t really target the region where the drug resistance mutations are found–they target the dynamic mechanism that some multi-drug-resistance mutants seem to utilize. Instead of putting a new sheath over a pair of scissors that want to stay open, we’re trying to restrain the handles to prevent cutting from occurring.
    In addition, the part about the computer simulations describes the background data that motivated this research. The data in our new paper is all from X-ray crystallographic experiments. We developed a new strategy for crystallographic screening that involves “plugging up” the active site with a known inhibitor and then using fragments to search for new binding sites that, when bound, stabilize the inhibited conformation.
    We must give Stefano Forli, Ph.D., my co-worker in Prof. Art Olson’s lab at TSRI, credit for making that beautiful image.
    Thank you for your interest,
    Dr. Alex L. Perryman

  2. MaverickNY

    Hello Dr Perryman, thank you for stopping by.
    Thank you for clarifying carefully regarding the active and inactive sites of the protease. I love the scissors analogy, that really is most helpful for visualising what is going on.
    On the Scripp site it wasn’t very clear who credit should be given to specifically at first sight as your eye is drawn to the graphic and the text above, not the very small print below. I have gladly added Dr Forli as credit for the beautiful picture.
    Good luck with the future research in this area, I look forward to hearing more as the project on the two compounds progresses.

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