L-nucleoside analogues as potential antimalarials that selectively target Plasmodium falciparum adenosine deaminase.
The L-stereoisomer analogues of D-coformycin selectively inhibited P. falciparum adenosine deaminase (ADA) in the picomolar range (L-isocoformycin, Ki 7 pM; L-coformycin, Ki 250 pM). While the L-nucleoside analogues, L-adenosine, 2,6-diamino-9-(L-ribofuranosyl)purine and 4-amino-1-(L-ribofuranosyl)pyrazolo[3,4-d]-pyrimidine were selectively deaminated by P. falciparum ADA, L-thioinosine and L-thioguanosine were not. This is the first example of 'non-physiological' L-nucleosides that serve as either substrates or inhibitors of malarial ADA and are not utilised by mammalian ADA.
Brown
D M
DM
School of Biochemistry and Molecular Genetics, University of New South Wales, Sydney, Australia.
Netting
A G
AG
Chun
B K
BK
Choi
Y
Y
Chu
C K
CK
Gero
A M
AM
D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000963:Antimetabolites / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D003070:Coformycin / Q000031:analogs & derivatives*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004912:Erythrocytes / Q000201:enzymology / Q000469:parasitology; D006801:Humans; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013379:Substrate Specificity
D058892:Adenosine Deaminase Inhibitors; D000962:Antimalarials; D000963:Antimetabolites; D004791:Enzyme Inhibitors; D009705:Nucleosides; D015800:Protozoan Proteins; D003070:Coformycin