Original Article FGI-104: a broad-spectrum small molecule inhibitor of viral infection
Michael S. Kinch, Abdul S. Yunus, Calli Lear, Hanwen Mao, Hanson Chen, Zena Fesseha, Guangxiang Luo, Eric A. Nelson, Limin Li, Zhuhui Huang, Michael Murray, William Y. Ellis, Lisa Hensley, Jane Christopher-Hennings, Gene G. Olinger, Michael Goldblatt
Functional Genetics Inc., 708 Quince Orchard Road, Gaithersburg, MD 20882, USA; US Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA; Department of Microbiology, Immunology and Molecular Genetics University of Kentucky, Lexington, KY, USA; Veterinary Science Department, Center for Infectious Disease Research and Vaccinology, South Dakota State University, Brookings, SD 57007-1396, USA; Hepatitis Research Program, Southern Research Institute, Frederick, MD 21701, USA; Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
Received December 29, 2008; accepted January 3, 2009; available online January 5, 2009
Abstract: The treatment of viral diseases remains an intractable problem facing the medical community. Conventional antivirals focus upon selective targeting of virus-encoded targets. However, the plasticity of viral nucleic acid mutation, coupled with the large number of progeny that can emerge from a single infected cells, often conspire to render conventional antivirals ineffective as resistant variants emerge. Compounding this, new viral pathogens are increasingly recognized and it is highly improbable that conventional approaches could address emerging pathogens in a timely manner. Our laboratories have adopted an orthogonal approach to combat viral disease: Target the host to deny the pathogen the ability to cause disease. The advantages of this novel approach are many-fold, including the potential to identify host pathways that are applicable to a broad-spectrum of pathogens. The acquisition of drug resistance might also be minimized since selective pressure is not directly placed upon the viral pathogen. Herein, we utilized this strategy of host-oriented therapeutics to screen small molecules for their abilities to block infection by multiple, unrelated virus types and identified FGI-104. FGI-104 demonstrates broad-spectrum inhibition of multiple blood-borne pathogens (HCV, HBV, HIV) as well as emerging biothreats (Ebola, VEE, Cowpox, PRRSV infection). We also demonstrate that FGI-104 displays an ability to prevent lethality from Ebola in vivo. Altogether, these findings reinforce the concept of host-oriented therapeutics and present a much-needed opportunity to identify antiviral drugs that are broad-spectrum and durable in their application. (AJTR812004).
Key Words: Antiviral, HCV, Ebola virus, HBV, hepatitis, HIV