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Encyclopedia > Vidarabine
Chemical structure of vidarabine
Chemical structure of vidarabine

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

Contents


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 [1]. The anti-viral activity of vidarabine was first described by M. Privat de Garilhe and J. De Rudder in 1964 [2]. 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 [3]. It was Dr. Richard Whitely in 1976 where the clinical effectiveness of vidarabine was first realised, and vidarabine was used in the treatment of many viral diseases [2]. Nucleosides are glycosylamines made by attaching a nucleobase to a ribose ring. ... It has been suggested that Porifera/Temp be merged into this article or section. ... Ribose Ribose is a five carbon sugar (pentose) that is critical to living creatures. ... Cytarabine is a shortened form of cytosine arabinoside, a commonly used chemotherapy agent used mainly in the treatment of leukemia and non-Hodgkin lymphoma. ... Antiviral drugs are a class of medication used specifically for treating viral infections. ... In colloquial use, herpes virus refers to the herpes simplex virus, particularly when transmitted sexually. ...


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 [4]. Half-Life is a science fiction first-person shooter computer game developed by Valve Software and published by Sierra Entertainment in 1998, based on a heavily-modified Quake game engine. ...


Mode of Action


Image File history File links Download high resolution version (949x476, 25 KB)Vidarabine Mechanism File history Legend: (cur) = this is the current file, (del) = delete this old version, (rev) = revert to this old version. ...


The Mechanism of Action of Vidarabine


Vidarabine works by interfering with the synthesis of viral DNA [5]. 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 [6]. 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 [6].


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 [7]. This metabolite still possesses antiviral activity, but is 10-fold less potent than vidarabine [8]. 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 [9]. 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 [8]. 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. Aciclovir (INN) or aciclovir (USAN), marketed as Zovirax®, is one of the main antiviral drugs. ... Ganciclovir sodium (Cytovene®) is an antiviral medication used to treat cytomegalovirus (CMV) infections. ... DNA polymerase 3D structure. ... Deamination is the removal of an amine group from a molecule. ... Hypoxanthine is a naturally occurring purine derivative, and one of the products of the action of xanthine oxidase on xanthine, though more normally in purine degradation, hypoxanthine is oxidized by xanthine oxidase to form xanthine. ... Human kidneys viewed from behind with spine removed The kidneys are bean-shaped excretory organs in vertebrates. ... Urine is liquid waste excreted by the kidneys and is produced by the process of filtration. ... The varicella-zoster virus (VZV), also known as human herpesvirus 3 (HHV-3), is one of the eight herpesviruses known to affect humans (and other vertebrates). ...


Synthesis/preparation/isolation


Vidarabine has been synthesised using E. coli bacterial cells [10], 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. [11]. Binomial name Escherichia coli T. Escherich, 1885 Escherichia coli (usually abbreviated to E. coli) is one of the main species of bacteria that live in the lower intestines of warm-blooded animals (including birds and mammals) and are necessary for the proper digestion of food. ... Glycosylation is the process or result of addition of saccharides to proteins and lipids. ...


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 [8], 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 [12]. 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. Ribonucleic acid (RNA) is a nucleic acid polymer consisting of covalently bound nucleotides. ... Acquired immunodeficiency syndrome, or acquired immune deficiency syndrome (or acronym AIDS or Aids), is a collection of symptoms and infections resulting from the specific damage to the immune system caused by infection with the human immunodeficiency virus (HIV). ... Aciclovir (INN) or aciclovir (USAN), marketed as Zovirax®, is one of the main antiviral drugs. ... Leukopenia or leukocytopenia refers to a decrease in the number of circulating white blood cells (leukocytes) in the blood. ... Thrombocytopenia (or -paenia, or thrombopenia in short) is the presence of relatively few platelets in blood. ...


Bibliography


[1] Kijjoa, A.; Sawangwong, P. Drugs and Cosmetics from the Sea. Mar. Drugs. 2004, 2, 73-82.


[2] Field, H. J.; De Clercq, E. Antiviral Drugs – a short history of their discovery and development. Microbiology Today. 2004, 31, 58-61.


[3] White, O. D.; Fenner, F. J. Medicinal Virology. 3rd Ed.


[4] Waterson, A. P. Recent Advances in Clinical Virology (2).


[5] Merck Manual. 17th Ed. Chapter 154, p.1127-1128.


[6] McGuigan, C. Antiviral Chemotherapy – Cardiff University, 3rd Year Pharmacy Notes Lecture Notes.


[7] Whitley, R. J.; Tucker, B. C.; Kinkel, A. W.; Barton, N. H.; Pass, R. F.; Whelchel, J. D.; Cobbs, C. G.; Diethelm, A. G.; Buchanan, R. A. Pharmacology, Tolerance, and Antiviral Activity of Vidarabine Monophosphate In Humans.


[8] Burgers Medicinal Chemistry and Drug Discovery. 6th Ed.


[9] BIAM - L'Ecole Nationale Supérieure des Mines de Paris http://www.biam2.org//www/Sub1767.html#SubIndic.


[10] Roshevskaia, L. A.; Barai, V. N.; Zinchenko, A. I.; Kvasiuk, E. I.; Mikhailopulo, L. A. Preparative synthesis of the antiviral nucleoside 9-beta-D-arabinofuranosyladenine by using bacterial cells. Antibiot. Med. Biotekhnol. 1986, 31(3), 174-8.


[11] Wang, Z.; Prudhomme, D. R.; Buck, J. R.; Park, M.; Rizzo, C. J. Stereocontrolled syntheses of deoxyribonucleosides via photoinduced electron-transfer deoxygenation of benzoyl-protected ribo- and arabinonucleosides. J Org Chem. 2000, 65(19), 5969-85.


[12] Drug Information Online - http://www.drugs.com/MMX/Vidarabine.html.


--Denurb 21:36, 19 Mar 2005 (UTC)

Antivirals (ATC J05A) edit
Anti-herpesvirus agents   Acyclovir · Cidofovir · Docosanol · Famciclovir · Foscarnet · Fomivirsen · Ganciclovir · Idoxuridine · Penciclovir · Trifluridine · Tromantadine · Valaciclovir · Valganciclovir · Vidarabine
Anti-influenza agents Amantadine · Oseltamivir · Peramivir · Rimantadine · Zanamivir
 
Antiretroviral drugs   NRTIs Zidovudine · Didanosine · Stavudine · Zalcitabine · Lamivudine · Abacavir · Tenofovir
NNRTIs   Nevirapine · Efavirenz · Delavirdine
PIs Saquinavir · Indinavir · Atazanavir · Ritonavir · Nelfinavir · Amprenavir · Lopinavir · Tipranavir
 
Other antiviral agents Fomivirsen · Enfuvirtide · Imiquimod · Interferon · Ribavirin · Viramidine

  Results from FactBites:
 
Vidarabine Drug Information, Professional (1261 words)
Vidarabine is not indicated for the treatment of infections caused by RNA viruses or adenoviruses, in other infections (bacterial, fungal, chlamydial), or in nonviral trophic ulcers.
Vidarabine is rapidly deaminated by adenosine deaminase to arabinosyl hypoxanthine (ara-hx).
Vidarabine may be administered concurrently with antibiotics (gentamicin, erythromycin, and chloramphenicol) and corticosteroids (prednisolone and dexamethasone).
  More results at FactBites »

 
 

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