Title : Therapeutic intervention of Bunyavirus induced hemorrhagic fever and cardiopulmonary disease
Viruses from different families in the order Bunyavirales contains highly contagious and deadly viruses, having no cure at present. For example, hantaviruses from the family Hantaviridae are negative stranded emerging RNA viruses and category A pathogens that cause serious illness when transmitted to humans through aerosolized excreta of infected rodents. Hantavirus infections cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) with mortality rates of 15% and 50%, respectively. Annually 150,000-200,000 cases of hantavirus infections are reported worldwide, and there is no treatment for this viral illness. The mortality rate of rift valley fever virus from the family Phenuiviridae can go as high as 60% in certain out breaks. The mortality rate of Heartland virus, another member of the family Phenuiviridae is 30%. Crimean Congo hemorrhagic fever virus (CCHFV) (Nairoviridae) has a mortality rate of 40%. La Crosse virus from the family Peribunyaviridae, especially the California serogroup, causes very serious encephalitis that changes the mental status in most infected patients. There are numerous other Bunyaviruses that cause serious human illnesses with bad prognosis because of the lack of vaccine and antiviral therapeutics. Thus, the need of the hour is to develop a broad spectrum antiviral therapeutic that selectively targets Bunyaviruses and improves the prognosis of their deadly diseases. Through our basic research efforts we identified the interaction between hantavirus nucleocapsid protein and viral mRNA 5’ UTR as a novel target for therapeutic intervention of hantaviruses. Using a high throughput screening approach, we identified a lead inhibitor that binds to the nucleocapsid protein, disrupts the N protein-UTR interaction and inhibits hantavirus replication in cells. The recent X-ray crystal structure revealed that hantavirus N protein shares structural homology with other Bunyaviruses nucleocapsid proteins. Consistent with the structural conservation of the target (N protein), we asked whether the identified lead inhibitor inhibits the replication of other Bunyaviruses. To this end, NIH tested our lead inhibitor against multiple viruses from diverse virus families. Interestingly, the lead inhibitor specifically inhibited all the tested viruses from the order Bunyavirales, such as Rift valley fever virus, Heartland virus, LaCrosse virus, and Hazara virus, which is a model virus used for studying CCHFV disease. The lead inhibitor did not show any effect upon the viruses from nine other families, demonstrating its specificity for Bunyaviruses Our research program is focused to use a combination of approaches including medicinal chemistry, X-ray crystallography, biochemistry, in vivo reporter assays and anti-viral testing to synthesize the derivatives of the lead inhibitor, having high target binding affinity and improved antiviral efficacy. The goal is to identify several drug like candidates that have strong and broad spectrum anti-viral activity. These drug like candidates will be tested for anti-Bunyavirus activity in animal models.