Arenaviruses are responsible for hemorrhagic fevers with high mortality. Effective therapies against Lassa fever virus (LASV) and Argentine hemorrhagic fever virus (Junin, JUNV) infections are urgently needed to address public health and national security concerns. Intervention strategies directed at the arenavirus envelope glycoprotein (GPC) provide a rational basis for the development of novel antiviral agents. We have recently demonstrated that an interaction between the ectodomains of the GPC fusion subunit (G2) and the unusual stable signal peptide (SSP) is essential for pH-dependent activation of GPCmediated membrane fusion. Interestingly, our preliminary results strongly suggest this interaction is targeted by small-molecule compounds (SIGA Technologies) that act to stabilize the pre-fusion GPC complex against low pH activation, thereby preventing virus entry. Importantly, a prototype inhibitor ST-193 has been shown to protect against lethal LASV infection in guinea pigs. We have established a collaboration with SIGA to capitalize on our knowledge of GPC and these promising lead compounds, in order to identify a broadspectrum arenavirus therapeutic for clinical development.
The specific aims of this proposal are: 1. To identify and characterize molecular determinants of the SSP-G2 interface that are responsible for the antiviral activity of SIGA fusion inhibitors. We will examine the contributions of individual sidechains to membrane-fusion activity and its inhibition. We will explore the role of sequence variation in JUNV and LASV in imparting species specificity to these compounds. Drug-resistant isolates derived in cell culture will be used to identify sidechains important for antiviral activity. 2. To characterize structural features of SIGA inhibitors that contribute to their antiviral activity. We will investigate chemical derivatives of lead compounds to define structure-activity relationships that determine potency and breadth of inhibition. We will also capitalize on the structural diversity of four distinct chemical classes of SIGA inhibitors to model a common pharmacophore using computational methods. 3. To evaluate the therapeutic efficacy of selected inhibitors. Optimized, drug-like compounds will be used in guinea pig models of pre-symptomatic JUNV and LASV infection to determine therapeutic efficacy. These studies will be important in the selection of a compound for non-human primate studies in accordance with the FDA Two-Animal Rule for IND filing and clinical development. This work fits within the RMRCE IRF-Viral Therapeutics, and interacts with RP 3.4.

Public Health Relevance

Arenaviruses are responsible for hemorrhagic fevers with high mortality. Effective therapies against Lassa fever, Argentine hemorrhagic fever and others are urgently needed to address ongoing public health and Category A biodefense concerns. The goal of this project is to develop potent and broadly active smallmolecule inhibitors that prevent arenavirus envelope glycoprotein-mediated entry into the host cell. These compounds will be useful for the treatment of arenavirus infection and disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
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Colorado State University-Fort Collins
Fort Collins
United States
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Lehman, Stephanie S; Mladinich, Katherine M; Boonyakanog, Angkana et al. (2016) Versatile nourseothricin and streptomycin/spectinomycin resistance gene cassettes and their use in chromosome integration vectors. J Microbiol Methods 129:8-13
Knudson, Susan E; Cummings, Jason E; Bommineni, Gopal R et al. (2016) Formulation studies of InhA inhibitors and combination therapy to improve efficacy against Mycobacterium tuberculosis. Tuberculosis (Edinb) 101:8-14
Charley, Phillida A; Wilusz, Jeffrey (2016) Standing your ground to exoribonucleases: Function of Flavivirus long non-coding RNAs. Virus Res 212:70-7
Phillips, Aaron T; Rico, Amber B; Stauft, Charles B et al. (2016) Entry Sites of Venezuelan and Western Equine Encephalitis Viruses in the Mouse Central Nervous System following Peripheral Infection. J Virol 90:5785-96
Westover, Jonna B; Sefing, Eric J; Bailey, Kevin W et al. (2016) Low-dose ribavirin potentiates the antiviral activity of favipiravir against hemorrhagic fever viruses. Antiviral Res 126:62-8
Shankar, Sundaresh; Whitby, Landon R; Casquilho-Gray, Hedi E et al. (2016) Small-Molecule Fusion Inhibitors Bind the pH-Sensing Stable Signal Peptide-GP2 Subunit Interface of the Lassa Virus Envelope Glycoprotein. J Virol 90:6799-807
York, Joanne; Nunberg, Jack H (2016) Myristoylation of the Arenavirus Envelope Glycoprotein Stable Signal Peptide Is Critical for Membrane Fusion but Dispensable for Virion Morphogenesis. J Virol 90:8341-50
Rhodes, Katherine A; Schweizer, Herbert P (2016) Antibiotic resistance in Burkholderia species. Drug Resist Updat 28:82-90
Voge, Natalia V; Perera, Rushika; Mahapatra, Sebabrata et al. (2016) Metabolomics-Based Discovery of Small Molecule Biomarkers in Serum Associated with Dengue Virus Infections and Disease Outcomes. PLoS Negl Trop Dis 10:e0004449
Rico, Amber B; Phillips, Aaron T; Schountz, Tony et al. (2016) Venezuelan and western equine encephalitis virus E1 liposome antigen nucleic acid complexes protect mice from lethal challenge with multiple alphaviruses. Virology 499:30-39

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