Mechanism of RVFV nucleocapsid targeting drugs

Lodmell, John

Abstract

Rift Valley fever virus (RVFV) is a mosquito-borne emerging infectious agent with potential for major impacts on human and agricultural animal health. It is a CDC/USDA Category A Select Agent, and has been recognized by the World Organization for Animal Health as a high consequence pathogen with potential for global spread. There are no proven treatments for RVFV infections and there is no licensed vaccine that has been proven safe and effective. We recently identified 78 compounds in a novel molecular target high throughput screen that interfere with the interaction of RVFV nucleocapsid protein, N, and a target RNA. These compounds come from existing drug and drug-like molecule libraries and several of the compounds show measurable inhibition of RVFV replication in cell culture. We propose to ascertain the molecular mechanism of action of several of the most promising compounds. We will use biochemical, biophysical and genetic approaches to determine the binding site(s) for the compounds on N and we will determine whether they inhibit the specific RNA binding activity or the generic RNA binding activity that are both intrinsic to N. Specifically, we will determine whether the inhibitory compounds interfere directly with RNA binding, interfere with nucleocapsid protein oligomerization, or have a target that is distinct from either the RNA-protein or protein-protein interfaces using RNA and drug binding assays with wild-type and mutant nucleocapsid protein. The research promises benefits to the fields of biomedicine and agricultural science by expanding our understanding of virus growth and inhibition, and by making advances toward new drug therapies to combat RVFV infections.

Public Health Relevance

Rift Valley fever virus is an emerging infectious agent that is capable of causing severe sickness and death in humans and in livestock. There is no cure or treatment for the disease. The virus is currently found in Africa and the Arabian Peninsula, but it poses a risk for spread outside this region. In fact, several mosquito species capable of transmitting RVFV already exist in North America. The purpose of the work proposed here is to understand how a new group of compounds identified in a drug screen act to inhibit a particular step in the RVFV life cycle. Results of these studies could help to develop new drugs that combat RVFV infections in people or livestock.