Flaviviruses, Henipaviruses, and Filoviruses represent a significant threat to U.S. and worldwide populations both as emerging infectious agents as well as their inherent potential to be developed into bioterrorist weapons. Our goal is to identify, characterize, and develop effective antiviral immunotherapeutics that target novel innate immune signaling pathways to potentially enhance immunity to control infections caused by Category A, B, and C agents. We have harnessed a unique approach of identifying antiviral compounds that target the RIG-I-like Receptor (RLR) pathway and activate interferon regulating factor (IRF)-3 to induce antiviral activity against Hepatitis C virus (HCV), West Nile virus (WNV), encephalomyocarditis virus (EMCV), and Influenza. Initial Structure-Activity Relationship (SAR) studies have identified 2 lead candidates, KBD 1700/1 and KBD1800, as the most promising for further development as potent antivirals. Our program is designed to advance the development of these lead compounds as immunotherapeutics against WNV, Dengue, Ebola, and Nipah. To achieve this purpose, we will conduct the following studies on our 2 lead candidate classes: i) perform SAR to optimize their antiviral activity and pharmacological properties, ii) define their cellular responses and antiviral mechanism of action, and iii) assess their systems interactions as well as determine their antiviral and toxicological properties in relevant disease challenge models. These studies will significantly enhance our development of KBD 1700/1 and KBD1800 as immunotherapeutics that can be used in the general population to fight emergent disease as well as be employed as defense mechanisms against potential bioterrorist attacks. PUBLIC HEALTH RELEVANCE: WNV, Dengue, Ebola, and Nipah represent a significant threat to worldwide populations both as emerging infectious agents and as vectors that have the potential to be developed into bioterrorist weapons. The work proposed in this study will significantly advance the candidacy of 2 lead compounds in our targeted goal of developing antiviral immunotherapeutics that can be used to treat disease caused by Category A-C agents. The development of these compounds into successful therapeutics has the potential to enhance the health populations at risk to these emergent virus infections or to be developed as defenses against bioterrorist attack.