Inhibition of human cytomegalovirus proteinase by salcomine derivatives.
Salcomine, N,N'-bis(salicylidene)ethylene diamino-cobalt (II), and its derivatives were evaluated for their ability to inhibit selectively human cytomegalovirus (HCMV) proteinase activity. The 50% inhibitory concentration (IC50) of salcomine was 1.4 microM for HCMV proteinase, but > 200 microM for three other serine proteinases (trypsin, > 250 microM; chymotrypsin, 206 microM; and elastase, > 250 microM). Two salcomine derivatives also inhibited HCMV proteinase with IC50 values under 2 microM. Studies of the structure-activity relationship of salcomine-related compounds showed that the phenyl moiety and the spacer moiety (distance between the two amines) were instrumental in the inhibition of HCMV proteinase. Moreover, salcomine inhibited the growth of laboratory strain AD169 and three clinical isolates at a 50% effective concentration (EC50) range of 1.92-2.89 microM. These results show that salcomine derivatives are potent and selective inhibitors of HCMV proteinase and HCMV replication in cell culture. Salcomine derivatives appear to be worth pursuing as candidate drugs for the chemotherapy of HCMV infection.
Watanabe
S
S
Rational Drug Design Laboratories, Fukushima, Japan. shinya@rdl.co.jp
Konno
K
K
Shigeta
S
S
Yokota
T
T
D000998:Antiviral Agents / Q000494:pharmacology; D003587:Cytomegalovirus / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts; D006801:Humans; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000494:pharmacology*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014361:Trypsin Inhibitors / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D014361:Trypsin Inhibitors; D010196:Pancreatic Elastase; C003955:N,N-ethylenebis(salicylideneiminato)cobalt(II)