The general organization of the picornavirus genomes is to encode for P1-P2-P3 precursors giving rise to 4-3-4 mature products. Some picornavirus species, in addition, encode a leader protein (L) placed before P1 ( Figure 2 ) [22] . In the case of aphthoviruses, such as foot-and-mouth disease virus (FMDV), the L protein has proteolytic activity and it is known as L pro [42, 43] . During polyprotein synthesis L pro is the first protein synthesized and its autoproteolytic activity releases itself from the rest of the polypeptide chain. Thus, the only known hydrolysis executed by L pro on the polyprotein is to hydrolyze between its carboxy terminus and the amino terminus of VP4 ( Figure 2 ). Because L pro does not play a direct role in viral replication [44] and its protease activity has a limited impact in the viral polyprotein, this protease may be involved in the interaction with the hostcell [45] [46] [47] . Indeed, L pro also exhibits proteolytic activity on eIF4G acting at a position close to that of PV 2A pro (Figure 3 ) [48] [49] [50] . In the case of FMDV, the 2A protein is reduced to a small peptide of 18 residues that does not hydrolyze eIF4G; instead it induces the release of 2A from its carboxy terminus by a ribosomal skip mechanism [51, 52] . This model proposes that FMDV 2A modifies the activity of the ribosome to promote hydrolysis of the peptidyl(2A)-tRNA(Gly) ester linkage at the C-terminus of 2A, thereby releasing the polypeptide from the translational complex. However, not all L or 2A proteins from picornaviruses exhibit protease activity, since in the case of EMCV, which encodes both proteins, neither has been demonstrated to possess proteolytic activity [53] .