This project is directed to the development of small-molecule and peptidomimetic inhibitors for blocking Bacillus anthracis (anthrax), Yersinia pestis (plague), Variola major (smallpox and other pox viruses), and Clostridium botulinum, by targeting their respective toxins: LF and PA, YopH, CrmA, BoNT/C. In close collaboration with Projects Cores, we will use a combination of virtual and high-throughput screening and novel synthetic approaches guided by NMR-based drug design strategies for generating small-molecule and peptidomimetic inhibitors. Given the arsenal of techniques proposed in this project, we anticipate being able within the course of the program to identify and characterize high affinity inhibitors for most of the targeted toxins.