Pipeline

RetroVirox is building a proprietary product pipeline of novel small-molecules with antiviral and immunomodulatory properties.

HIV Immunomodulators for HIV Eradication

Over 35 million people worldwide are infected with HIV. Patients can be successfully treated with antiretroviral cocktails that achieve viral load reductions below levels of detection. However, infected individuals also carry in their genome copies of the HIV provirus in a state of latency. In this form, HIV can hide for decades within cells and tissues named “viral reservoirs”, where the virus remains virtually invisible to the patient’s immune system.

Due to the HIV’s ability to remain dormant, antiretroviral therapy must be administered throughout the patient’s lifetime. Treatment interruption results in rebound of the viral load, which often leads to the appearance of resistant strains that further complicate therapy. RetroVirox is developing immunomodulators as components of “kick and kill” strategies to eradicate HIV. In these approaches the dormant virus is first purged away from the viral reservoirs by activating latently-infected cells to produce viruses. The killing of these reactivated cells is then facilitated with small-molecules that enhance the ability of the immune system to recognize HIV antigens.

RetroVirox is developing small-molecule inhibitors to enhance the immune response against HIV and help eradicate infection using the patient’s own immune system. To do this scientists at RetroVirox have targeted a viral activity that eliminates the MHC-I human protein from the surface of infected cells. MHC-I is required to “present” viral antigens to the CD8-positive cells. These cells, also named “cytotoxic T lymphocytes (CTL)” are one of the most important tools utilize for the immune system to help clear viral infections, including HIV.

By eliminating MHC-I from infected cells HIV escapes the immune system and makes infected cells resistant to killing by the patient’s CTLs. Virus-mediated elimination of the MHC-I protein is not unique to HIV, and it has been demonstrated in other viruses, including herpesviruses and adenoviruses.

RetroVirox screened over 50,000 drug-like molecules to identify specific inhibitors of the HIV-mediated downmodulation of MHC-I.

These efforts have resulted in the successful identification of three lead inhibitors that are currently being optimizing for potency, specificity and ADME properties. When added to infected T cells in vitro (right figure) these inhibitors prevent the appearance of cells expressing low levels of MHC-I, as shown in flow cytometry analyses of the infected cultures (yellow areas). Cells with low levels of MHC-I are not present either in T cells infected with an HIV virus lacking Nef (second quadrant from right), the viral protein known to downmodulate MHC-I.

Over 800 analogs have been modified and screened to make these inhibitors more potent. Our efforts have characterized molecules with enhanced potency (single-digit nM EC50 values) and high selectivity indices (over 10,000). RetroVirox is now seeking partnerships to advance the preclinical development of these molecules (read more).