Broad-spectrum antiviral activities of neplanocin A, 3-deazaneplanocin A, and their 5'-nor derivatives.
The neplanocin A analogs, 3-deazaneplanocin A, 9-(trans-2',trans-3'-dihydroxycyclopent-4'-enyl)adenine (DHCA), and 9-(trans-2',trans-3'-dihydroxycyclopent-4'-enyl)-3-deazaadenine (DHCDA), all potent inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase, were studied for their broad-spectrum antiviral potential. 3-Deazaneplanocin A, DHCA, and DHCDA proved specifically effective against vesicular stomatitis virus, vaccinia virus, parainfluenza virus, reovirus, and rotavirus. Their selectivity was greater than that of neplanocin A, particularly against vesicular stomatitis virus and rotavirus. As could be expected from adenosine analogs that are directly targeted at AdoHcy hydrolase, 3-deazaneplanocin A, DHCA, and DHCDA were fully active in adenosine kinase-deficient cells, implying that their activity did not depend on phosphorylation by adenosine kinase. None of the AdoHcy hydrolase inhibitors showed selective activity against human immunodeficiency virus (type 1). 3-Deazaneplanocin A at a dose of 0.5 mg/kg per day conferred marked protection against a lethal infection of newborn mice with vesicular stomatitis virus.
De Clercq
E
E
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Cools
M
M
Balzarini
J
J
Marquez
V E
VE
Borcherding
D R
DR
Borchardt
R T
RT
Drach
J C
JC
Kitaoka
S
S
Konno
T
T
D000241:Adenosine / Q000494:pharmacology / Q000031:analogs & derivatives; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D006367:HeLa Cells; D051379:Mice; D012087:Reoviridae / Q000187:drug effects; D018108:Respirovirus / Q000187:drug effects; D012401:Rotavirus / Q000187:drug effects; D018139:Simplexvirus / Q000187:drug effects; D014616:Vaccinia virus / Q000187:drug effects; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; C054757:9-(2',3'-dihydroxycyclopent-4'-enyl)adenine; C054759:9-(2',3'-dihydroxycyclopent-4'-enyl)-3-deazaadenine; C048460:3-deazaneplanocin; C031096:neplanocin A; D000241:Adenosine