Therapeutic Areas
HIV
Human Immunodeficiency Virus type 1 (HIV-1) infects immune system cells, destroying or damaging their function, and causes Acquired Immune Deficiency Syndrome (AIDS). The progressive deterioration caused by the virus, characterized by the progressive loss of CD4+ helper T lymphocytes (T cells), eventually leaves the immune system unable to fight off infection and disease. Opportunistic infections, often associated the with severe immunodeficiency, take advantage of the depleted immune system.
In 2007, an estimated 33 million people were infected with an additional 6,800 new cases globally every day. Since the beginning of the AIDS epidemic, an estimated 25 million people have died from AIDS-related complications. (UNAIDS, 2008). The enormous need for effective therapies has driven the growth of a huge antiviral drug market currently worth $11 billion globally.
Despite the growth and maturity of the HIV drug market, approximately 15% of new HIV cases are resistant to at least one of the four classes of FDA approved drugs. AIDS patients also generate resistant virus over the course of treatment often leading to multi-drug resistant strains of HIV. Combination therapy is a difficult regimen to follow where 75% of patients experience on ore more serious side-effects. Non-compliance also exacerbates the drug resistance problem.
Therefore, at AGS we are developing an entirely new class of HIV therapeutic that is inherently less vulnerable to escape mutations by the virus, but can also be combined with other drugs to maintain effective treatment and enhance quality of life.
Targeting HIV
HIV develops drug resistance with relative ease because the molecular targets of current drugs are relatively unconstrained, allowing the virus to quickly develop escape mutations. In contrast, we are developing inhibitors that target HIV Ribonucleoprotein (RNP) complexes, essential HIV structures that presents multiple barriers to viral resistance.
Within the constraints of a 10kb genome that encodes only 15 proteins, HIV has evolved a remarkable system to overcome the problem of producing RNA for protein production and to the pass on its genetic material. After the HIV particle has invaded a host cell, it "hijacks" the cellular machinery and initiates production of viral RNA. Host cells have a series of checkpoints to ensure that proper production, processing, and export of RNA occurs in a specific order. Because HIV must produce RNA for both protein production and packaging into progeny virus particles, it has evolved systems to bypass the RNA regulatory mechanisms of the cell. Specific HIV RNP complexes that perform these essential activities are the molecular targets of our therapeutics.
Controlling HIV Resistance
HIV drug resistance is the ability of the virus to mutate and replicate even in the presence of antiviral drugs. The consequences include treatment failure, greater healthcare costs, the imperative to move to alternative treatments, and the spread of resistant strains of HIV to other patients. Thus, there is pressing need to create new drugs for the changing HIV virus. Targeting RNP complexes in HIV give three significant advantages over current classes of HIV drugs:
Disrupting structured viral RNA. Structural RNA forms highly conserved but inherently unstable molecules. The RNA component of an RNP complex is more sensitive to point mutations than genes that encode proteins, thus imposing a high barrier to drug resistance.
Disrupting cooperative assembly of the RNP complexes. Formation of HIV RNP complexes requires the proper assembly of multiple proteins on the RNA. These proteins are highly conserved and the RNA-binding domains are even more invariant suggesting that mutations in these proteins are not tolerated.
Essential proteins encoded in overlapping regions of the HIV-1 genome. By utilizing RNA as a structural component and encoding many essential components in overlapping sequences, the virus has exposed a vulnerable drug target. The HIV genome contains critical RNA structures that overlaps the most highly conserved region of essential genes. Mutations in overlapping regions are more likely deleterious to multiple HIV-1 components and are therefore selected against.