Metal chelators as antiviral agents.
Processes involving the creation and modification of oligomeric nucleotide substrates are key events in the replication cycles of many viruses, and have been successful targets for much pharmaceutical research. Because of high levels of intracellular divalent magnesium, and the high affinity of oxyanions for this hard Lewis acid, enzymes responsible for these transformations have evolved to use the divalent magnesium cation in their catalytic function. The interruption of enzyme function via active-site metal coordination has recently emerged as a viable approach to viral inhibition, and the most advanced programs in this field have now entered late-stage clinical trials, thus validating the approach. This review summarizes such programs that were initiated from alpha,gamma-diketo acid leads and that resulted in optimized candidates. Key relationships between structure and activity for successful high-affinity magnesium binding in the active site of these enzymes have been identified.
Gilead Sciences Inc, 333 Lakeside Drive, Foster City, CA 94404, USA. tkirschberg@gilead.com
Thorsten
T
Kirschberg
Jay
J
Parrish
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000627:therapeutic use*; D015195:Drug Design; D006801:Humans; D007502:Iron Chelating Agents / Q000737:chemistry / Q000627:therapeutic use*; D014777:Virus Diseases / Q000188:drug therapy*
D000998:Antiviral Agents; D007502:Iron Chelating Agents