The RNA capping machinery as an anti-infective target

Abstract

A number of different human pathogens code for their own enzymes involved in the synthesis of the RNA cap structure. Although the RNA cap structures originating from human and microbial enzymes are often identical, the subunit composition, structure and catalytic mechanisms of the microbial-encoded enzymes involved in the synthesis of the RNA cap structure are often significantly different from those of host cells. As a consequence, these pathogenic cap-forming enzymes are potential targets for antimicrobial drugs. During the past few years, experimental studies have started to demonstrate that inhibition of the RNA capping activity is a reasonable approach for the development of antimicrobial agents. The combination of structural, biochemical, and molecular modeling studies are starting to reveal novel molecules that can serve as starting blocks for the design of more potent and specific antimicrobial agents. Here, we examine various strategies that have been developed to inhibit microbial enzymes involved in the synthesis of the RNA cap structure, emphasizing the challenges remaining to design potent and selective drugs.

Figure 1

Structural and functional organization of the capping apparatus. (a) Schematic representation of the RNA triphosphatase, RNA guanylyltransferase, and RNA methyltransferase gene organization among different organisms. Both the mechanistical and structural conservation levels are correlated with the color index. (b) Crystal structures of the RNA triphosphatases from mouse (metal independent), S. cerevisiae (metal dependent), and Dengue virus (metal dependent). The corresponding Protein Data Bank (PDB) accession codes are indicated.