## 1 Introduction  
Foot-and-mouth disease (FMD), a highly contagious viral disease affecting cloven-hooved livestock as well as wildlife species, is caused by FMDV virus (FMDV). FMD has a great economic impact on the global livestock industry and undermines food security [1; 2]. According to the OIE (World Organization for Animal Health) report of 2017 [3], FMD is endemic in several regions of Asia, a great part of Africa and also Middle East countries. Moreover, the FMD-free countries (where the disease was previously eradicated) are under continuous threat of an incursion of FMD. In this case, outbreaks of the diseaserepresent approximately 1.5 billion dollars per year in losses. In endemic regions, the cost is estimated to be \(>\)6.5 billion dollars per year [1]. Therefore, the control and reduction of the impact of FMD will have a highly positive economic effect on both FMD-free and FMD-infected countries. FMDV is a member of the _Picornaviridae_ family and its genome consists of a positive-sense single-stranded RNA molecule, of around 8 Kb, that has a small peptide linked to its 5'-end called viral protein genome-linked or VPg. VPg plays a key role in the initiation of genome replication, acting as a primer for RNA synthesis [4]. Replication of the FMDV genome is mediated by a viral RNA-dependent RNA polymerase (RdRp), named 3 Dpol through a negative-sense RNA intermediate. RdRp uses VPg as a primer for both minus and plus strand RNA synthesis. The first step of the viral genome replication consists of the successive incorporation of two uridine-monophosphate residues to a highly conserved tyrosine residue (Tyr3) of VPg. This reaction, termed uridyylation, is also catalyzed by 3 Dpol using as template a small stem-loop structure (cis-acting replication element (cre) or 3B-uridyylation site (bus)) that is located within the 5'-untranslated region [5; 6; 7]. Hence, the hydroxyl group of Tyr3 forms a phosphodiester bond with the first UTP molecule to form VPgPU; then, VPgPU \"slides back\" one base-pair and a second UTP is incorporated to form VPgpUpU, which acts as a protein primer for the synthesis of the genomic RNA. Unlike other picornaviruses, which express a single VPg protein, the genome of FMDV encodes three similar but not identical VPg copies (VPg1, VPg2 and VPg3) [8] and all three of them are linked to the viral RNA [5; 9]. These VPgs are 23 or 24 amino acids long, can be uridyylated (Figure 1) and are active as replication primers [10]. Although deletion as well as insertion of one VPg gene still results in infective particle production, optimal viral RNA synthesis and FMDV viability require all three copies [2; 11; 12]. The x-ray crystal structures of the complexes between FMDV 3 Dpol and the uridyylated and non-uridyylated forms of VPg1 have been determined [12]. Both complexes showed that VPg1 is located inside the central cleft of the polymerase, positioning the hydroxyl group of Tyr3 to mimic the free 3'-hydroxyl group of a nucleic acid primer at the polymerase catalytic site [12]. Moreover, a combination of these crystal complexes with site-directed mutagenesis of 3 Dpol and chemical synthesis of mutant VPg proteins, allowed the determination of the importance of several residues of 3 Dpol for initiation of RNA synthesis [2; 12]. The structure of the complexes showed the positioning of 15 out of the 23 amino acids of VPg1. It was also possible to trace one or two additional poorly ordered VPg amino acids, exiting from the polymerase central cavity while the remaining six C-terminal residues were completely disordered [12]. Despite the key role of 3 Dpol in the life cycle of the FMDV, there are currently very few molecules described as inhibitors of the virus replication [13; 14; 15; 16; 17]. Among them, 5-fluoruridine triphosphate  
Figure 1: Amino acid sequence WebLogos of foot-and-mouth disease virus (FMDV) viral protein genome-linked (VPgs).