A Structure-Based Drug Discovery Strategy for Viral Replication Inhibitors
Our proprietary structural biology, enzymology and medicinal chemistry expertise enable us to develop novel antiviral agents. These technologies and our market-focused approach to drug discovery are designed to effectively create small molecule therapeutics that are safe, effective and convenient to administer.
Advantages of our Technology
Our technology provides a 3-D structure of inhibitor complexes at near-atomic resolution and immediate insight to guide SAR. This helps us identify novel binding sites and allows for a rapid turnaround of structural information through highly automated x-ray data processing and refinement.
Broad-Spectrum Antiviral Activity
For any given viral disease, there are different strains of viruses that cause the disease. In influenza there are three types of influenza viruses, A, B, and C. Influenza A and B viruses are significant human respiratory pathogens that cause seasonal flu. Influenza A viruses can also cause an influenza pandemic. Influenza C is a subtype of the influenza virus that tends to cause only mild illness and is not responsible for seasonal or pandemic infections. Our goal is to design and develop drug candidates that will be effective on the broadest possible range of viruses causing the disease.
Many antiviral drugs available today are effective only against certain strains of viruses and less effective or not effective at all against other strains. To address this problem, we are developing drug candidates that specifically target viral proteins involved in viral replication. Despite the various strains of virus that may exist, these replication enzymes are essentially identical (highly conserved) among all strains of a given virus. By targeting these conserved replication enzymes, our antiviral compounds are designed and tested to be effective against major virus strains. Replication enzymes are generally conserved not only among subtypes of a given virus but also among different viruses, creating an opportunity for the development of broad-spectrum antiviral drugs.
High Barrier to Resistance
Drug resistance is a major obstacle to developing effective antiviral therapies. Viruses can reproduce rapidly and in enormous quantities in infected human cells. During viral replication, random changes in the viral genome, called mutations, develop. If such a mutation occurs in a region of the viral genome that is targeted by a given antiviral therapy, that therapy may no longer be effective against the mutated virus. These mutated or “resistant” viruses can freely infect and multiply even in individuals who have received drug treatment. In some cases, resistant virus strains may even predominate. For example, in the 2009 swine influenza pandemic, the predominant strain was resistant to the best available therapies.
Our focus is on viral replication proteins that can overcome the obstacle of viral resistance. We identify and target critical components of viral replication proteins that are essential for function, therefore, sensitive to change. A mutation in these critical components is likely to inactivate the replication protein and, in turn, render the virus incapable of replicating. Because the mutated virus cannot propagate, it cannot effectively develop resistance to the enzyme inhibitors we employ. We test the effectiveness of our compounds against potential viral mutations and select compounds with the highest barrier to resistance.
Market Driven Product Profiles
Patients at risk for suffering from many viral infections have few effective antiviral treatments from which to choose. Furthermore, some available treatment options have characteristics that limit their market potential. They are either priced too high, poorly tolerated, inconvenient to administer, ineffective against some viral subtypes or prone to emergence of resistance.
In all of our programs our goal is to develop best-in-class broad-spectrum antiviral drugs with high barrier to drug resistance. An ideal product for an antiviral therapy would have at least the following characteristics:
- High barrier to viral resistance;
- Effective against all viral subtypes that cause disease;
- Fast onset of action and/or shortened treatment time;
- Good safety and tolerability profile; and
- Ease of administration, for example, a pill.
Our technology is based on the work of our Chief Scientist and Chairman of our Scientific Advisory Board, Dr. Roger Kornberg.
Dr. Kornberg was awarded the 2006 Nobel Prize for Chemistry for his work to visualize a replication enzyme called RNA polymerase in action. Using techniques called protein cocrystallization and x-ray crystallography, Dr. Kornberg and his colleagues generated three dimensional pictures similar to the one on the right of RNA being transcribed by an RNA polymerase.
We are leveraging Dr. Kornberg's expertise in these methods to identify and develop new antiviral compounds. Using these methods, our scientists are able to:
- Directly visualize how viral replication enzymes work;
- Identify key parts of these enzymes to target;
- Design compounds to block the function of these enzymes, thereby preventing viruses from replicating; and
- Discover novel nucleosides and other compounds, which inhibit viral replication.