Structure-assisted discovery of Variola major H1 phosphatase inhibitors

Variola major virus, the causative agent of smallpox, encodes the dual-specificity H1 phosphatase. Because this enzyme is essential for the production of mature virus particles, it is an attractive molecular target for the development of therapeutic countermeasures for this potential agent of bioterrorism. As a first step in this direction, the crystal structure of H1 phosphatase has been determined at a resolution of 1.8 Å. In silico screening methods have led to the identification of several small molecules that inhibit Variola H1 phosphatase with IC₅₀ values in the low micromolar range. These molecules provide novel leads for future drug development.