Enzymatic properties of the unnatural beta-L-enantiomers of 2',3'-dideoxyadenosine and 2',3'-didehydro-2',3'-dideoxyadenosine.
The beta-L-enantiomers of 2',3'-dideoxyadenosine and 2',3'-didehydro-2',3'-dideoxyadenosine have been stereospecifically synthesized. In an attempt to explain the previously reported antiviral activities of these compounds, their enzymatic properties were studied with respect to adenosine kinase, deoxycytidine kinase, adenosine deaminase, and purine nucleoside phosphorylase. Adenosine deaminase was strictly enantioselective and favored beta-D-ddA and beta-D-d4A, whereas adenosine kinase and purine nucleoside phosphorylase had no apparent substrate properties for the D- or L-enantiomers of beta-ddA or beta-d4A. Human deoxycytidine kinase showed a remarkable inversion of the expected enantioselectivity, with beta-L-ddA and beta-L-d4A having better substrate efficiencies than their corresponding beta-D-enantiomers. Our results demonstrate the potential of beta-L-adenosine analogues as antiviral agents and suggest that deoxycytidine kinase has a strategic importance in their cellular activation.
Pélicano
H
H
UMR 5626 du CNRS, Département de Chimie Organique Fine, Université Montpellier-2 des Sciences et Techniques du Languedoc, France.
Pierra
C
C
Eriksson
S
S
Gosselin
G
G
Imbach
J L
JL
Maury
G
G
D000243:Adenosine Deaminase / Q000378:metabolism; D000248:Adenosine Kinase / Q000378:metabolism; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D002417:Cattle; D003842:Deoxycytidine Kinase / Q000378:metabolism; D016048:Dideoxyadenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D004355:Drug Stability; D006678:HIV / Q000187:drug effects; D006515:Hepatitis B virus / Q000187:drug effects; D006801:Humans; D011683:Purine-Nucleoside Phosphorylase / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D000998:Antiviral Agents; D016048:Dideoxyadenosine; C075923:2'3'-didehydro-2'3'-dideoxyadenosine; D011683:Purine-Nucleoside Phosphorylase; D000248:Adenosine Kinase; D003842:Deoxycytidine Kinase; D000243:Adenosine Deaminase