Two closely related types of small molecules that blockstrand transfer catalyzed by recombinant integrase havebeen identified. Both types show in vitro antiviral activity.The diketo acids1 inhibit strand transfer catalyzed by recombinantintegrase with an IC50 less than 0.1μm.Mutations that conferred resistance to the diketo acidsmapped near conserved residues in the IN enzyme. Thisfinding demonstrates that the compounds have a highlyspecific mechanism of action. X-ray crystallography of thebound tetrazole derivative revealed that the inhibitorwas centered in the active site of IN near acidic catalyticresidues.
