Inhibitors against DNA Polymerase I Family of Enzymes: Novel Targets and Opportunities.

Simple Summary: DNA polymerases are essential enzymes for the growth and survival of a cell. These enzymes replicate and/or repair the cellular genome. Some DNA polymerases have been associated with specific diseases. For example, Y-family DNA polymerases have been associated with cancer. Family A polymerases (typified by E. coli DNA polymerase I) have been extensively studied, primarily to understand the mechanism of DNA replication. Human mitochondrial DNA polymerase γ and DNA polymerase θ are exceptions as they have roles in genetic diseases and cancer, respectively. However, recent studies have uncovered novel roles of Family A polymerases. Thus, polymerase θ has been shown to conduct reverse transcriptase activity, an activity displayed by retroviruses' (such as HIV) reverse transcriptases. The association of these polymerases with diseases makes them attractive therapeutic targets against diseases such as cancer and bacterial/parasitic infections. This perspective is focused on Family A polymerases as potential therapeutic targets for the development of new classes of antibiotics, antimalarial, and anticancer drugs. These new drugs could be used either alone or in combination with current interventions to circumvent drug-resistance. Modern techniques, such as artificial intelligence and docking of millions of drug-like compounds, can expedite the discovery of new interventions targeting Family A polymerases. DNA polymerases replicate cellular genomes and/or participate in the maintenance of genome integrity. DNA polymerases sharing high sequence homology with E. coli DNA polymerase I (pol I) have been grouped in Family A. Pol I participates in Okazaki fragment maturation and in bacterial genome repair. Since its discovery in 1956, pol I has been extensively studied, primarily to gain deeper insights into the mechanism of DNA replication. As research on DNA polymerases advances, many novel functions of this group of polymerases are being uncovered. For example, human DNA polymerase θ (a Family A DNA pol) has been shown to synthesize DNA using RNA as a template, a function typically attributed to retroviral reverse transcriptase. Increased interest in drug discovery against pol θ has emerged due to its roles in cancer. Likewise, Pol I family enzymes also appear attractive as drug-development targets against microbial infections. Development of antimalarial compounds targeting apicoplast apPOL, an ortholog of Pol I, further extends the targeting of this family of enzymes. Here, we summarize reported drug-development efforts against Family A polymerases and future perspective regarding these enzymes as antibiotic targets. Recently developed techniques, such as artificial intelligence, can be used to facilitate the development of new drugs. [ABSTRACT FROM AUTHOR]