Molecular basis for the antiviral and anticancer activities of unnatural L-beta-nucleosides.

Abstract:

As a general rule, enzymes act on only one enantiomer of a chiral substrate and only one of the enantiomeric forms of a chiral molecule may bind effectively at the catalytic site, displaying biological activity. In recent years, some exceptions have been found among viral and cellular enzymes involved in the synthesis of deoxynucleoside triphosphates and in their polymerisation into DNA. Examples are: herpes virus thymidine kinases, cellular deoxycytidine kinase and deoxynucleotide kinases, human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, hepatitis B virus (HBV) DNA polymerase and, to a lesser extent, some cellular DNA polymerases. The lack of enantioselectivity allows herpes simplex virus (HSV) thymidine kinase and cellular deoxycytidine kinase to phosphorylate the unnatural L-beta-enantiomers of D-thymidine and D-deoxycytidine, respectively, or of their analogues to monophosphate. This phosphorylation represents the first and often the rate-limiting step of their activation to triphosphates. The L-triphosphates can then exert antiviral (anti-HSV, anti-Human cytomegalovirus, anti-HIV-1, anti-HBV) and anticancer activities. Although only one L-nucleoside (3TC) has so far gained United States of America Food and Drug Administration (USA FDA) approval for clinical use against HIV-1, other L-enantiomers of nucleoside analogues, which have shown antiviral or anticancer activity in cell cultures are in clinical trials. Their resistance to enantioselective enzymes, such as thymidine phosphorylase, thymidylate synthase, (deoxy)-cytidine and dCMP deaminases, and their lower affinity for the mitochondrial thymidine kinase can ensure a higher selectivity and lower cytotoxicity with respect to those exerted by their corresponding natural D-enantiomers and might be exploited to solve problems arising during chemotherapy, such as metabolic inactivation, cytotoxicity and drug-resistance.

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