Mechanism of inhibition of a poxvirus topoisomerase by the marine natural product sansalvamide A

被引:72
作者
Hwang, Y
Rowley, D
Rhodes, D
Gertsch, J
Fenical, W
Bushman, F
机构
[1] Salk Inst Biol Studies, Infect Dis Lab, La Jolla, CA 92037 USA
[2] Univ Calif San Diego, Scripps Inst Oceanog, Ctr Marine Biotechnol & Biomed, La Jolla, CA 92093 USA
关键词
D O I
10.1124/mol.55.6.1049
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
引用
收藏
页码:1049 / 1053
页数:5
相关论文
共 23 条
[1]  
AMIDON GL, 1994, ANNU REV PHARMACOL, V34, P321
[2]  
BLACKBURN RK, 1993, DRUG METAB DISPOS, V21, P573
[3]   BIOLOGICAL EFFECTS OF CYCLOSPORIN-A - NEW ANTILYMPHOCYTIC AGENT [J].
BOREL, JF ;
FEURER, C ;
GUBLER, HU ;
STAHELIN, H .
AGENTS AND ACTIONS, 1976, 6 (04) :468-475
[4]   NEW DIMENSIONS IN NATURAL-PRODUCTS RESEARCH - CULTURED MARINE MICROORGANISMS [J].
DAVIDSON, BS .
CURRENT OPINION IN BIOTECHNOLOGY, 1995, 6 (03) :284-291
[5]  
EICHLER J, 1995, MOL DIVERS, V1, P233
[6]   BIOACTIVE MARINE METABOLITES .33. CYCLOTHEONAMIDES, POTENT THROMBIN INHIBITORS, FROM A MARINE SPONGE THEONELLA SP [J].
FUSETANI, N ;
MATSUNAGA, S ;
MATSUMOTO, H ;
TAKEBAYASHI, Y .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1990, 112 (19) :7053-7054
[7]   SCREENING OF CYCLIC PEPTIDE PHAGE LIBRARIES IDENTIFIES LIGANDS THAT BIND STREPTAVIDIN WITH HIGH AFFINITIES [J].
GIEBEL, LB ;
CASS, RT ;
MILLIGAN, DL ;
YOUNG, DC ;
ARZE, R ;
JOHNSON, CR .
BIOCHEMISTRY, 1995, 34 (47) :15430-15435
[8]   MOLLUSCUM CONTAGIOSUM [J].
GOTTLIEB, SL ;
MYSKOWSKI, PL .
INTERNATIONAL JOURNAL OF DERMATOLOGY, 1994, 33 (07) :453-461
[9]   EUKARYOTIC DNA TOPOISOMERASES-I [J].
GUPTA, M ;
FUJIMORI, A ;
POMMIER, Y .
BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION, 1995, 1262 (01) :1-14
[10]  
Hansen MST, 1998, GENET ENG P, V20, P41