L-Nucleoside Analogues as Potential Antimalarials That Selectively Target Plasmodium Falclparum Adenosine Deaminase

Abstract

The L-stereoisomer analogues of D-coformycin selectively inhibited P. falciparum adenosine deaminase (ADA) in the picomolar range (L-isocoformycin, K _i 7 pM; L-coformycin, K _i 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.