TY - JOUR T1 - Mechanism of Inhibition of a Poxvirus Topoisomerase by the Marine Natural Product Sansalvamide A JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1049 LP - 1053 DO - 10.1124/mol.55.6.1049 VL - 55 IS - 6 AU - Young Hwang AU - David Rowley AU - Denise Rhodes AU - Jeff Gertsch AU - William Fenical AU - Frederic Bushman Y1 - 1999/06/01 UR - http://molpharm.aspetjournals.org/content/55/6/1049.abstract N2 - At present no antiviral agents are available for treatment of infection by the pathogenic poxvirus molluscum contagiosum virus (MCV). Here we report the identification and characterization of an inhibitor active against the virus-encoded type-1 topoisomerase, an enzyme likely to be required for MCV replication. We screened a library of marine extracts and natural products from microorganisms using MCV topoisomerase assays in vitro. The cyclic depsipeptide sansalvamide A was found to inhibit topoisomerase-catalyzed DNA relaxation. Sansalvamide A was inactive against two other DNA-modifying enzymes tested as a counterscreen. Assays of discrete steps in the topoisomerase reaction cycle revealed that sansalvamide A inhibited DNA binding and thereby covalent complex formation, but not resealing of a DNA nick in a preformed covalent complex. Sansalvamide A also inhibits DNA binding by the isolated catalytic domain, thereby specifying the part of the protein sensitive to sansalvamide A. These data specify the mechanism by which sansalvamide A inhibits MCV topoisomerase. Cyclic depsipeptides related to sansalvamide A represent a potentially promising chemical family for development of anti-MCV agents. ER -