Drug Discovery Opinion

There has been interest in the DNA polymerase sliding clamp as an antibacterial target for the last 15 years. Sliding clamp proteins, found in all organisms, encircle DNA (and slide along it!) and tether polymerases to enable rapid and processive DNA replication. The proteins are known as proliferating cell nuclear antigen (PCNA) in eukaryotes and as the β-clamp in prokaryotes. In PCNA the clamp is composed of three subunits of two domains each, whilst the bacterial β-clamp is assembled from two subunits of three domains. Although the overall structures of the eukaryotic and prokaryotic clamps are similar, there is no detectable sequence homology.

In a paper to be published in the August 12^th edition of PNAS, the authors disclose a small molecule inhibitor of the E.coli β-clamp, RU7, which differentially inhibits polymerases II, III and IV.

RU7 selectively inhibits Pol III in β-dependent replication assays, with no activity in the eukaryotic PCNA system. The compound, which has modest potency, was identified by screening for compounds able to displace a Pol III peptide from the β-clamp. The authors have also determined the co-crystal structure of RU7 bound to the clamp (pdb identifier 3d1g), paving the way for structure-based design.

PDB:3D1G

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