Discovery of Small-Molecule Inhibitors That Target Hantavirus Nucleocapsid Proteins
Nilshad Salim1, Erdong Cheng1, Safder Saeed1, Steven Rodgers2, Jeffrey Aubé2 Anuradha Roy2 and Mohammad Mir1
1 The University of Kansas Medical Center, 3901 Rainbow Blvd Kansas City, KS 66160. 2 The University of Kansas, 1450 Jayhawk Blvd, Lawrence, KS 66045.
Hantaviruses are enveloped negative stranded viruses that belong to the Bunyaviridae family and are carried by reservoir hosts such as rodents, shrews, moles and bats. While Hantavirus infections in reservoir hosts are often asymptomatic it causes severe renal, cardiac and pulmonary failure when transmitted to humans. To date, Hantavirus diseases present a motility rate of 30 – 50 % and the recent outbreak in Yosemite National Park in California, USA in 2012 had a motility rate of ~30 %. Currently, there is no FDA approved cure or vaccine to protect against Hantavirus associated diseases. In this study a High-Throughput Screen (HTS) was employed to identify antiviral lead compounds that disrupt RNA binding to Sin nombre virus nucleocapsid protein (Np). Np is a multifunctional protein that plays pivotal roles during virus propagation in hosts and inactivation of Np would profoundly affect viral functions. HTS identified several compound clusters that consistently inhibited Np functions and one particular compound K-31 from cluster-3 inhibited Andes virus replication by ~96 % in cell culture models. After examining a multitude of compounds related to cluster-3 we identified a scaffold structure and obtained structure activity relationships (SARs) that would enable us to further develop these compounds. Furthermore, K-31 also inhibited HCV virus propagation in cell culture with high potency displaying broad spectrum antiviral activity. Current work in this project involves testing the efficiency of K-31 against a variety of pathogenic viruses for broad spectrum antiviral activity and the potency of K-31 in Syrian hamster models for protection against Hantavirus associated diseases.