FGI-104: A Broad-Spectrum Small Molecule Inhibitor of Viral Infection

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 broadspectrum 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.

Antiviral Activity of a Small-Molecule Inhibitor of Filovirus Infection

“…A component of the vps system, TSG101, has been shown to be involved with both EBOV (15, 17)-and MARV (22)-derived VP40 to mediate viral budding and release. Recently, a broad-spectrum small-molecule inhibitor of EBOV, FGI-104, has been described, and TSG101 was reported as a possible molecular target (11). To ask if TSG101 might be targeted by FGI-103, the interaction of EBOV VP40 and TSG101 was modeled using a solid-phase assay in which His-tagged TSG101 was immobilized on enzyme-linked immunosorbent assay plates via an anti-His tag.…”

Development of experimental and early investigational drugs for the treatment of Ebola virus infections

“…In the FGI-104 experiment, groups of 10 mice were administered an IP injection of FGI-104 at a dose of 10 mg/kg, beginning 2 h after infection, followed by 10 additional, identical daily doses spaced over the next 10 days. This strategy protected 100% of mice (10 survivors out of 10) [79]. In the FGI-103 study, groups of 10 mice were given a single IP injection of FGI-103 at a dose of 10 mg/kg, beginning 24 h after infection.…”

Emerging Targets and Novel Approaches to Ebola Virus Prophylaxis and Treatment

“…High throughput screening systems have also aided in identifying three small molecule inhibitors of EBOV infection: FGI-103 131 , FGI-104 132 and FGI-106 133 . These compounds have provided 80~100% protection in mice challenged with EBOV (Table 2).…”