• Retroviruses belong to the Retroviridae family of viruses, their genetic material consisting of ribonucleic acid (RNA), instead of deoxyribonucleic acid (DNA). As such, RNA viruses initiate the duplication of their genetic material via the enzyme reverse transcriptase to produce DNA from its RNA genome. The DNA is then incorporated into the host’s genome by an integrase enzyme. Retroviruses are known to lead to a variety of diseases and debilitating conditions in both humans and animals, as well as a range of viral infections: (cancer, paralysis, wasting, ataxia, arthritis, dementia and neuropathy).
• Human Immunodeficiency Virus (HIV), the virus that causes Acquired Immune Deficiency Syndrome (AIDS), is one example of a retrovirus. HIV/AIDS weakens a person’s ability to fight infections and cancer due to a compromised immune system. As of 2008, nearly 35 million people worldwide were infected with the HIV virus, with a corresponding rate of infection of 2 million additional people per annum. As a consequence of this disease, nearly 2 million people a year die from AIDS. Approximately 27 years after the initial diagnosis of HIV, there are more than 2 dozen clinically approved drugs currently used to combat HIV/AIDS. These therapies fall into 4 categories: Cell Entry Inhibitors (i. Fusion Inhibitors and ii. Co-receptor Inhibitors), Reverse Transcription Inhibitors, Integrase Inhibitors and Protease Inhibitors.
• HIV-1 capsid assembly is a late essential step in the retroviral life cycle and is not targeted by antiretrovirals currently in use. Immature HIV capsid formation has been achieved within the cell-free protein synthesis (CFPS) in a heterologous translation system programmed with HIV gag p55. Capsid formation by CFPS has been studied in considerable detail with a number of assembly intermediates identified, ordered into a pathway, and corroborated in HIV-infected mammalian cells. We established an ELISA-based small molecule screen of the entire pathway, and have evaluated over 20,000 drug-like small molecules conforming to Lipinski’s Rules. The CC50 and IC50 values of the hits identified were determined in the T cell line C8166-SEAP, and live virus cell culture inhibition of wild-type HIV-1 NL4-3, HIV-1 BRU, HIV-2 Rod and SIVmac239 retroviral strains. SAR optimization of the lead series PAV8802 is currently ongoing, with emphasis on improving the pharmacokinetic and safety profiles.