Interactions between arenavirus proteins and small molecule inhibitors of infection

Author

Emily L. Messina

Year of Award

2013

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Other Degree Name/Area of Focus

Integrative Microbiology and Biochemistry

Department or School/College

Department of Chemistry and Biochemistry

Committee Chair

Jack Nunberg

Commitee Members

Steve Lodmell, Scott Wetzel, Brent Ryckman, Keith Parker

Abstract

Arenaviruses are globally distributed, negative-sense, single-stranded RNA viruses which persist in specific rodent host species. Of the 32 known arenaviruses, 10 have been associated with human disease. Of these, Lassa, Junín, Machupo, Guanarito, and Sabia viruses cause severe hemorrhagic fevers. The only current option for the treatment of arenavirus infection is the off-label use of ribavirin. However, ribavirin is associated with severe side effects. Clearly, there exists a need for the study of arenavirus biology and of novel drugs for the treatment of arenaviral infection. My work focused on two attractive targets for inhibition of infection: the arenaviral RNA-dependent RNA polymerase, to block replication of the viral genome, and the arenaviral envelope glycoprotein (GPC), to prevent delivery of the viral genome to the cytosol. We showed that the novel purine analogue, T-705, is effective at inhibiting the replication of highly pathogenic arenaviruses in vitro. Further, we showed that T-705 specifically blocks viral transcription without significantly reducing cellular transcription activity. We also explored the interactions between the SSP and G2 subunits within GPC. We demonstrated that the first transmembrane region of SSP is a functional subdomain and that the interactions between this region and the transmembrane region of G2 are essential to fusion activity. Further, we demonstrated that residues in this subdomain are key to drug sensitivity. We also worked to characterize the arrangement between the transmembrane regions using cysteine-scanning mutagenesis and we engineered a construct linking the first transmembrane region of SSP to the transmembrane region of G2 to serve as a potential model for studying the interactions between these two regions.

Recommended Citation

Messina, Emily L., "Interactions between arenavirus proteins and small molecule inhibitors of infection" (2013). Graduate Student Theses, Dissertations, & Professional Papers. 10756.
https://scholarworks.umt.edu/etd/10756