Neutral sphingomyelinase-inhibiting guanidines prevent herpes simplex virus-1 replication.
We synthesized a series of new guanidinium derivatives and studied the inhibitory activity on both neutral sphingomyelinase and herpes simplex virus-1 (HSV-1) replication. The lipophilic quality of the molecules was found to be correlated with the inhibitory potential of the compounds. Undecylidene-aminoguanidine was superior to derivatives with 10, 8 or 6 carbon atoms whereas propylidene-aminoguanidine was completely inactive. Decylidene-aminoguanidine was the most active derivative, with 10 carbon atoms. Various cyclic saturated isomers were inferior to the linear molecule. Aromatic cyclic residues were superior to saturated cyclic residues. The most active compound was a derivative containing 11 carbon atoms, undecylidene-aminoguanidine (C11AG), which inhibited the replication of HSV-1 by 50% at a concentration of 2.6 microM while cytotoxic adverse effects were only observed at a concentration of 31 microM. Expression of immediate early gene ICP-4 and concomitantly of HSV-1 specific DNA replication was found to be a target of C11AG. This result suggests that C11AG interferes with cellular signal transduction mechanisms that regulate expression of HSV-1 immediate early genes. C11AG was shown to inhibit neutral sphingomyelinase without affecting phospholipase A2, phosphatidylcholine-specific phospholipase C and phospholipase D.
Amtmann
E
E
Research Center for Diagnostic and Experimental Therapy, Department of Immunoregulation and Cancer Therapy, Heidelberg, Germany.
Zöller
M
M
Schilling
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G
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis / Q000302:isolation & purification; D003864:Depression, Chemical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017781:Genes, Immediate-Early / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D000882:Haplorhini; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D006801:Humans; D010740:Phospholipases / Q000037:antagonists & inhibitors; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects*
C500287:C11AG compound; D004791:Enzyme Inhibitors; D006146:Guanidines; D004247:DNA; D010740:Phospholipases; D013108:Sphingomyelin Phosphodiesterase