Foot-and-mouth disease virus (FMDV) is the etiologic agent of FMD, an infectious and sometimes fatal viral disease that affects cloven-hoofed animals. The FMDV genome encodes a large polyprotein, the first component of which is the Leader protein. Unusually, within the picornavirus family, the FMDV Leader protein (L<sup>pro</sup>) is a protease. This protease induces a very rapid inhibition of host cell cap-dependent protein synthesis within infected cells. This results from cleavage of the cellular translation initiation factor eIF4G. Translation of the viral RNA is unaffected since it is dependent on an internal ribosome entry site (IRES) that directs cap-independent translation initiation. L<sup>pro</sup> also releases itself from the virus capsid precursor (at the L/P1 junction). The aim of this project is to identify amino acids that are essential for eIF4G cleavage but not for the self-processing. This study may allow design of mutant viruses that are deficient in blocking host cell responses to infection (e.g. interferon induction) and assist in the rational design of antiviral agents targeting this process.