Inhibition of cytomegalovirus in vitro and in vivo by the experimental immunosuppressive agent leflunomide.
Despite progress in antiviral chemotherapy, cytomegalovirus (CMV) remains a major cause of morbidity and mortality among pharmacologically immunosuppressed transplant recipients, frequently engaging the clinician in a struggle to balance graft preservation with control of CMV disease. Leflunomide, an inhibitor of protein kinase activity and pyrimidine synthesis, is an experimental immunosuppressive agent effective against acute and chronic rejection in animal models. Herein we summarize our recent studies demonstrating that leflunomide inhibits the production of multiple clinical CMV isolates (including multi-drug-resistant virus) in both human fibroblasts and endothelial cells. In contrast to all other anti-CMV drugs currently in use, leflunomide does not inhibit viral DNA synthesis, but rather appears to interfere with virion assembly. Finally, preliminary studies in a rat model suggest that this agent reduces viral load in vivo. These findings imply that leflunomide, an effective immunosuppressive agent, shows potential to concurrently attenuate a major complication of immunosuppression, CMV disease, by a novel mechanism of antiviral activity.
Waldman
W J
WJ
Department of Pathology, The Ohio State University College of Medicine and Public Health, Columbus, Ohio, USA. waldman.1@osu.edu
Knight
D A
DA
Blinder
L
L
Shen
J
J
Lurain
N S
NS
Miller
D M
DM
Sedmak
D D
DD
Williams
J W
JW
Chong
A S
AS
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects* / Q000502:physiology; D003586:Cytomegalovirus Infections / Q000188:drug therapy / Q000821:virology; D004279:DNA, Viral / Q000096:biosynthesis; D004352:Drug Resistance, Microbial; D018432:Drug Resistance, Multiple; D004730:Endothelium, Vascular / Q000166:cytology / Q000821:virology; D005347:Fibroblasts / Q000821:virology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007555:Isoxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D000077339:Leflunomide; D051381:Rats; D014529:Uridine / Q000494:pharmacology
D000998:Antiviral Agents; D004279:DNA, Viral; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D000077339:Leflunomide; D014529:Uridine