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.

Antivirals for the Treatment of Lassa Fever

Lassa fever is a viral hemorrhagic fever endemic to West Africa. Lassa fever virus (LASV), the causative agent, is a member of the arenavirus family. Lassa fever was first identified in the town of Lassa (Nigeria) in 1969. Outbreaks of the disease have been observed in Nigeria, Liberia, Sierra Leone, Guinea, and the Central African Republic. Lassa fever is the second most important viral hemorrhagic fever in humans after Ebola, although Lassa claims many more lives than Ebola due to its higher incidence. Estimates vary widely on the number of LASV infections per year from 300,000 to 500,000, to as high as 2-3 million. Lassa fever is estimated to cause between 5,000 to 10,000 deaths every year. To put these numbers into perspective, Ebola has infected only about 31,000 people since it first emerged in 1976, equivalent to 325 infections per year or about one thousandth of the annual infections estimated with LASV.

No vaccine is available for LASV. Treatment options are extremely limited and focus primarily on ribavirin, a broad-spectrum antiviral drug that has been used with limited success in LF and display many side effects. New treatments are much needed.

At RetroVirox we have initiated a program to identify inhibitors of Lassa virus. Over 55,000 molecules have been screened against a prototypic arenavirus (LCMV) and lead inhibitors with anti-LASV activity have been identified in antiviral assays using Biosafety level 4 containment.

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 500 analogs have been modified and screened to make these inhibitors more potent. Our efforts have characterized molecules with enhanced potency (20-50nM EC50 values) and high selectivity indices (over 4,000). RetroVirox is now seeking partnerships to advance the preclinical development of these molecules (read more).