Vidarabine

Vidarabine is an anti-viral drug which is active against herpes simplex and varicella zoster viruses.

How the drug was discovered
In the 1950’s two nucleosides were isolated from the Caribbean sponge Tethya crypta: spongothymidine and spongouridine; which contained an arabinoside sugar rather than a ribose. These compounds led to the synthesis of a new generation, sugar modified nucleoside analog: vidarabine, and the related compound: cytarabine. In 2004 these were the only marine related compounds in clinical use. The anti-viral activity of vidarabine was first described by M. Privat de Garilhe and J. De Rudder in 1964. It was the first nucleoside analog antiviral to be given systemically and was the first agent to be licensed for the treatment of systematic herpes virus infection in man. It was Dr. Richard Whitley in 1976 where the clinical effectiveness of vidarabine was first realised, and vidarabine was used in the treatment of many viral diseases.

Vidarabine (9-β-D-ribofuranosyladenine) is an analog of adenosine with the D-ribose sugar, replaced with D-arabinose. As you can see from figure 1.1 that it is a stereoisomer of adenosine. It has a half life of 60 minutes, and its solubility is 0.05%, and is able to cross the blood-brain barrier (BBB) when converted to its active metabolite.

Mode of Action


The Mechanism of Action of Vidarabine

Vidarabine works by interfering with the synthesis of viral DNA. It is a nucleoside analog and therefore has to be phosphorylated to be active. This is a three step process in which vidarabine is sequentially phosphorylated by kinases to the triphosphate ara-ATP. This is the active form of vidarabine and is both an inhibitor and a substrate of viral DNA polymerase. When used as a substrate for viral DNA polymerase, ara-ATP competitively inhibits dATP leading to the formation of ‘faulty’ DNA. This is where ara-ATP is incorporated into the DNA strand replacing many of the adenosine bases. This results in the prevention of DNA synthesis, as phosphodiester bridges can longer to be built, destabilizing the strand. Vidarabine triphosphate (ara-ATP) also inhibits RNA polyadenylation; preventing polyadenylation essential for HIV-1 and other retroviruses; and S-adenosylhomocysteine hydrolase, preventing transmethylation reactions. Uniquely to vidarabine, the diphosphorylated vidarabine (ara-ADP) also has an inhibitory effect. Other nucleoside analogs need to be triphosphorlated to give any antiviral effect, but ara-ADP inhibits the enzyme ribonucleotide reductase. This prevents the reduction of nucleotide diphosphates, causing a reduction of viral replication.

Mode of Resistance
Vidarabine is more toxic and less metabolically stable than many of the other current antivirals such as acyclovir and ganciclovir. Viral strains resistant to vidarabine show changes in DNA polymerase. It is prone to deamination by adenosine deaminase to a hypoxanthine. This metabolite still possesses antiviral activity, but is 10-fold less potent than vidarabine. 60% of vidarabine eliminated by the kidney is excreted as arabinosyle-hypoxanthine in the urine. Some breakdown of the purine ring may also occur, forming uric acid. Structural modifications of vidarabine have proven partially effective at blocking deamination, such as replacement of the amine with a methoxy group (ara-M). This results in about a 10-fold greater selectivity against Varicella Zoster Virus than ara-A, however analog of vidarabine is inactive against other viruses due to it not being able to be phosphorylated. The use of an inhibitor of adenosine deaminase to increase the half life of vidarabine has also been tried, and drugs such as dCF and EHNA have been used with a small amount of success.

Synthesis/preparation/isolation
Vidarabine has been synthesised using E. coli bacterial cells, and by using Vorbrüggen glycosylation with a Lewis acid catalyst. This involves the reaction of a base with a sugar and is used to synthesise natural ßβ-nucleosides.

Selectivity
Vidarabine is less susceptible to the development of drug resistant strains than other antivirals such as IDU, and has been used successfully in the treatment of IDU resistant viral strains. The half life of the active triphosphate metabolite (ara-ATP) is three times longer in HSV-infected cells compared with uninfected cells, however the mechanism of selectivity is not known.

Current clinical Indication
Vidarabine is an antiviral, active against herpes viruses, poxviruses, rhabdoviruses, hepadnarviruses and some RNA tumour viruses. A 3% ophthalmic ointment Vira-A is used in the treatment of acute keratoconjuctivitis and recurrent superficial keratitis caused by HSV-1 and HSV-2. Vidarabine is also used to treat herpes zoster in AIDS patients, reducing lesions formation and the duration of viral shedding. Many of the previous uses of vidarabine have been superseded by acyclovir, due to the hospitalisation required for intra venous dosing, and acyclovir has a higher selectivity, lower inhibitory concentration and higher potency. Toxic side effects are rare, but have been reported with high concentrations of vidarabine, such as nausea, vomiting, leukopenia and thrombocytopenia in patients receiving high intravenous doses daily.