Acyclovir {9-[(2-hydroxyethoxy)methyllguanine} is an acyclic guanine nucleoside analogue that is widely used clinically as an antiherpetic agent. Its limited absorption in humans after oral administration prompted the search for prodrugs. A congener, referred to as 6-deoxyacyclovir {2-amino-9-[(2-hydroxyethoxy)methyl]-9H-purine}, was synthesized and found to be 18 times more water soluble than was acyclovir. Surprisingly, this congener was readily oxidized to acyclovir by xanthine oxidase (EC 1.2.3.2). It was also oxidized by aldehyde oxidase (EC 1.2.3.1) largely to 8-hydroxy-6-deoxyacyclovir {2-amino-8-hydroxy-9-[(2-hydroxyethoxy)methyl]-9H-purine} and then to 8-hydroxyacyclovir {2-amino-6,8-dihydroxy-9[(2-hydroxyethoxy)methylj-9H-purine}. 6-Deoxyacyclovir and the major products of its oxidation by aldehyde oxidase lacked appreciable activity against herpes simplex type I in vitro. On the basis of these results, it was apparent that the success of 6-deoxyacyclovir as a prodrug in vivo would depend upon how well its desired activation by xanthine oxidase competed with the nonactivating oxidations by aldehyde oxidase.In rats dosed orally with 6-deoxyacyclovir, absorption was extensive and the major urinary metabolite was acyclovir. In two human volunteers, urinary excretions of acyclovir were 5-6 times greater than those typically observed after administration of equivalent doses of acyclovir itself. The areas under the plasma concentration-time curves for acyclovir were also 5-6 times greater. Plasma levels of acyclovir peaked soon after ingestion of the prodrug, indicating rapid absorption and metabolic conversion. These results suggested that 6-deoxyacyclovir might have clinical usefulness as a prodrug of acyclovir suitable for oral administration.Acyclovir {9-[(2-hydroxyethoxy)methylJguanine; Zovirax} is a clinically useful antiherpetic agent (1, 2). Intravenous (3, 4), oral (5), or topical (6, 7) administration provides-effective therapy. Only 15-20% of the dose is typically absorbed in humans after oral administration (8). This degree of absorption is adequate for efficacy against herpes simplex infections (5). However, greater absorption might be important in therapy against less sensitive viruses such as varicella-zoster virus (9). The clinical experience to date clearly indicates that although acyclovir represents a major therapeutic advance in the treatment of herpetic infections, a means of enhancing gastrointestinal absorption would significantly extend its usefulness.Considerable effort has been expended in attempts to find a prodrug that is well absorbed after oral administration and then converted to acyclovir. Esterification of the hydroxyl group of the (2-hydroxyethoxy)methyl moiety of acyclovir has been an approach taken by two separate laboratories (10,11). Unfortunately, those esters that have been tested showed no significant improvement in absorption after oral dosing (unpublished results).The 6-deoxy-6-amino congener of acyclovir {2,6-diamino-9-[(2-hydroxyethoxy)methyl]-9H-purine} (...
A xanthosine-inducible enzyme, inosine-guanosine phosphorylase, has been partially purified from a strain of Escherichia coli K-12 lacking the deo-encoded purine nucleoside phosphorylase. Inosine-guanosine phosphorylase had a particle weight of 180 kilodaltons and was rapidly inactivated by p-chloromercuriphenylsulfonic acid (p-CMB). The enzyme was not protected from inactivation by inosine (Ino), 2'-deoxyinosine (dlno), hypoxanthine (Hyp), Pi, or c-D-ribose-1-phosphate (Rib-1-P). Incubating the inactive enzyme with dithiothreitol restored the catalytic activity. Reaction with p-CMB did not affect the particle weight. Inosine-guanosine phosphorylase was more sensitive to thermal inactivation than purine nucleoside phosphorylase. The half-life determined at 45°C between pH 5 and 8 was 5 to 9 min. Phosphate (20 mM) stabilized the enzyme to thermal inactivation, while Ino (1 mM), dIno (1 mM), xanthosine (Xao) (1 mM), Rib-i-P (2 mM), or Hyp (0.05 mM) had no effect. However, Hyp at 1 mM did stabilize the enzyme. In addition, the combination of P1 (20 mM) and Hyp (0.05 mM) stabilized this enzyme to a greater extent than did Pi alone. Apparent activation energies of 11.5 kcal/mol and 7.9 kcal/mol were determined in the phosphorolytic and synthetic direction, respectively. The pH dependence of Ino cleavage or synthesis did not vary between 6 and 8. The substrate specificity, listed in decreasing order of efficiency (V/Ki), was: 2'-deoxyguanosine, dIno, guanosine, Xao, Ino, 5'-dIno, and 2',3'-dideoxyinosine. Inosine-guanosine phosphorylase differed from the deo operon-encoded purine nucleoside phosphorylase in that neither adenosine, 2'-deoxyadenosine, nor hypoxanthine arabinoside were substrates or potent inhibitors. Moreover, the E. coli inosine-guanosine phosphorylase was antigenically distinct from the purine nucleoside phosphorylase since it did not react with any of 14 monoclonal antisera or a polyvalent antiserum raised against deo-encoded purine nucleoside phosphorylase.Nucleoside phosphorylases catalyze the reversible phosphorolysis of either purine or pyrimidine nucleosides, yielding pentose-1-phosphate and the nucleobase. Three nucleoside phosphorylases expressed by Escherichia coli have been well characterized (10,12,20,24). The udp gene product, uridine phosphorylase (EC 2.4.2.3), and the deoA gene product, thymidine phosphorylase (EC 2.4.2.4), catalyze the phosphorolysis and synthesis of pyrimidine ribonucleosides and 2'-deoxyribonucleosides, respectively. The third enzyme, purine nucleoside phosphorylase (E.C. 2.4.2.1), encoded by the deoD gene of the deo operon, cleaves and synthesizes both purine ribonucleosides and 2'-deoxyribonucleosides.The nucleobase specificity of purine nucleoside phosphorylase is dependent on the source from which it is isolated. Hyp, Gua, Xan, and their respective nucleosides are efficient substrates for most mammalian purine nucleoside phosphorylases, whereas Ade and Ade nucleosides are extremely inefficient substrates (14,28,32). The nucleobase specificity of purine nucleoside...
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