VACVase Inhibitors

VACVase inhibitors represent a class of chemical compounds designed to interfere with the enzymatic activity of viral-associated uracil-DNA glycosylases (UDGs). UDGs play a critical role in base excision repair, a highly conserved mechanism within cells that identifies and excises uracil residues from DNA strands. These residues arise due to either spontaneous deamination of cytosine or erroneous incorporation of uracil during replication. The removal of uracil is essential to prevent mutations and maintain genomic stability. In viruses like the vaccinia virus (VACV), UDGs are similarly vital for proper replication and infection processes. By inhibiting VACVase, a specific viral UDG, VACVase inhibitors interfere with the viral replication cycle, thereby limiting viral propagation.

At the molecular level, VACVase inhibitors function by binding to the active site of the enzyme, blocking its ability to catalyze the hydrolysis of the N-glycosidic bond between uracil and the sugar backbone in the DNA molecule. This disruption of uracil excision hinders subsequent DNA repair and replication steps required for viral genome synthesis. Structurally, many VACVase inhibitors are designed to mimic uracil, thereby competing with the natural substrate of the enzyme. Others may exploit allosteric inhibition, inducing conformational changes in the enzyme's structure that reduce its catalytic efficiency. The specificity of these inhibitors towards viral UDGs over cellular UDGs is a critical focus in the design of these molecules, ensuring that their interaction selectively affects viral replication without disrupting host DNA repair mechanisms. Thus, VACVase inhibitors are an intriguing class of molecules that contribute to understanding the intricate relationship between viral enzymes and the processes essential for viral survival.