Francesc Xavier Ruiz, Assistant Research Professor in Professor Eddy Arnold’s laboratory at CABM, has been awarded a $35,000 grant from the New Jersey Health Foundation to develop novel drugs targeting the
acquired immune deficiency syndrome (AIDS), caused by the human immunodeficiency virus (HIV). HIV/AIDS came into the spotlight as a silent, deadly, and mysterious killer during the 1980s. 40 years later, AIDS has been transformed into a chronic disease, mainly because of antiretroviral therapy (ART) and preventive treatment (PrEP). However, even amid the COVID-19 pandemic, it remains a major threat to global health and at the state level (∼40 million people infected in the world, ~40,000 people in New Jersey and 8th state in US in new HIV cases diagnosed).
The incredibly rapid evolution of HIV, paired with the frequent exposure to antiretroviral drugs, allows the virus to mutate (“adapt”) its genome to resist drugs; that is, to render them much less effective. Of all antiretroviral drugs, half of them target reverse transcriptase (RT), a central protein from HIV that transforms the viral RNA genome to DNA, which can integrate into the human genome. After that, HIV can reappear once antiretroviral therapy is stopped or made less effective by resistance to drugs.
In this project, we—co-principal investigators F. Xavier Ruiz and Eddy Arnold—try to stay ahead of the virus following a two-pronged strategy. We seek the classic 'running faster' strategy: designing new drugs acting directly on the virus, including those viruses resisting the drugs used now in patients. Antiretrovirals targeting RT are either “nucs” (they mimic the building blocks of DNA, halting DNA extension) or “non-nucs”, that affect RT by making it stiffer and slowing its action. We have recently found the way nucleotide-competing RT inhibitors (NcRTIs, chemically different to the nucs but binding in the same place as them) stop RT action. We have now designed compounds that are hybrids of nucs and NcRTIs, but are envisioned to work differently to both, and may not have the same type of resistance raised by nucs. We are also trying a second approach based on the 'jumping higher' strategy: instead of targeting the virus action, we are disrupting an essential interaction between RT and the cellular protein eukaryotic elongation factor 1A (eEF1A), normally involved in protein translation, co-opted by HIV to help in viral propagation.
The goal of this project is to solve structures of RT with the new designed nuc-NcRTI hybrid molecules and of the RT-eEF1A complex, as well as with compounds disrupting the complex. These detailed snapshots will allow discovery of RT inhibitors acting through new mechanisms, paving the way for development of new antivirals. Besides, we anticipate that nuc-NcRTIs can be repurposed to block polymerases from other dangerous RNA viruses of pandemic potential.