The dioxolane analog of 3TC, troxacitabine is currently in a Phase II/III clinical trial for third-line treatment of acute myelogenous leukemia (AML), a blood cancer. The pharmacological potential of l -nucleoside analogs has been recently reviewed ( 3–5 ). An additional six d -nucleoside analogs have been approved as AIDS therapeutics, and it is customary for patients to receive both l - and d -enantiomer anti-HIV agents simultaneously. Since this discovery, two non-physiologic l -nucleoside analogs have been approved for treatment of human acquired immune deficiency syndrome (AIDS). Quite unexpectedly, however, it was demonstrated that it is the l -component of the racemic mixture (±)-BCH-189, which possesses significantly better anti-human immunodeficiency virus (HIV) properties than its d -enantiomeric counterpart ( 1, 2 ). It has, therefore, been widely accepted that enzymes that must correctly bind ligands and catalyze chemistry on their respective substrates, will invariably show high chiral selectivity. This is the first analysis of the structural basis for activation of l -nucleoside analogs, providing further impetus for discovery and clinical development of new agents in this molecular class.Ĭhirality is a hallmark of biological systems: proteins are composed of l -amino acids and DNA and RNA are composed of β- d -nucleotides.
Second, the pseudo-symmetry of nucleosides and nucleoside analogs in combination with their conformational flexibility allows the l - and d -enantiomeric forms to adopt similar shapes when bound to the enzyme. First, the nucleoside-binding site tolerates substrates with different chiral configurations by maintaining virtually all of the protein-ligand interactions responsible for productive substrate positioning. The capability of dCK to phosphorylate both d - and l -nucleosides and nucleoside analogs derives from structural properties of both the enzyme and the substrates themselves. Our studies reveal how dCK, which normally catalyzes phosphorylation of the natural d -nucleosides, can efficiently phosphorylate substrates with non-physiologic chirality. The first step in activating these agents is catalyzed by dCK. Herein, we report the crystal structures of human deoxycytidine kinase (dCK) in complex with the l -nucleosides (−)-β-2′,3′-dideoxy-3′-thiacytidine (3TC)-an approved anti-human immunodeficiency virus (HIV) agent-and troxacitabine (TRO)-an experimental anti-neoplastic agent. These pro-drugs achieve pharmacological activity only after enzyme-catalyzed conversion to their tri-phosphorylated forms.
L -nucleoside analogs represent an important class of small molecules for treating both viral infections and cancers.
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