Antimalarial activity of a 4',5'-unsaturated 5'-fluoroadenosine mechanism-based inhibitor of S-adenosyl-L-homocysteine hydrolase.
A 4',5'-unsaturated 5'-fluoroadenosine inhibitor of S-adenosyl-L-homocysteine hydrolase (SAH hydrolase; EC 3.3.1.1), MDL 28842, was found to inhibit markedly the growth of Plasmodium falciparum in vitro and Plasmodium berghei in mice. Inhibition of P. berghei growth was associated with a large increase in the concentration of S-adenosyl-L-homocysteine (SAH) in the erythrocytes of the mice treated with MDL 28842. This increase in SAH was due apparently to inhibition of the mouse erythrocyte SAH hydrolase activity, because SAH hydrolase activity was undetectable in either P. berghei or P. falciparum isolated from infected erythrocytes, although enzyme activity was readily detected in mouse erythrocyte extracts. Therefore, MDL 28842 probably inhibits plasmodial growth indirectly by adversely changing the milieu of the host erythrocyte. SAH hydrolase represents a worthwhile target for the future development of potent inhibitors for the chemotherapy of malaria.
Merrell Dow Research Institute, Cincinnati, OH 45215.
A J
AJ
Bitonti
R J
RJ
Baumann
E T
ET
Jarvi
J R
JR
McCarthy
P P
PP
McCann
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D043383:Adenosylhomocysteinase; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D004912:Erythrocytes / Q000378:metabolism; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000097:blood; D008288:Malaria / Q000097:blood / Q000188:drug therapy*; D015394:Molecular Structure; D010962:Plasmodium berghei / Q000187:drug effects / Q000254:growth & development; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development; D012435:S-Adenosylhomocysteine / Q000097:blood
D000962:Antimalarials; C065189:4',5'-didehydro-5'-deoxy-5'-fluoroadenosine; D012435:S-Adenosylhomocysteine; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine