Vidarabine
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Vidarabine or 9-β-D-arabinofuranosyladenine (ara-A) is an
Discovery
In the 1950s two
The drug was first synthesized in 1960 in the Bernard Randall Baker lab at the Stanford Research Institute (now SRI International).[2]
The drug was originally intended as an anti-cancer drug.[2] The anti-viral activity of vidarabine was first described by M. Privat de Garilhe and J. De Rudder in 1964.[3] It was the first nucleoside analog antiviral to be given systemically and was the first agent to be licensed for the treatment of systemic herpes virus infection in humans.[4] It was University of Alabama at Birmingham researcher and physician Richard J. Whitley in 1976 where the clinical effectiveness of vidarabine was first realized, and vidarabine was used in the treatment of many viral diseases.[3]
Vidarabine is an analog of adenosine with the D-ribose 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.[5]
Mode of action
The Mechanism of action of vidarabine
Vidarabine works by interfering with the synthesis of viral DNA.[6] 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.[7]
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 no 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.[citation needed]
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.[7]
Mode of resistance
Vidarabine is more toxic and less metabolically stable than many of the other current antivirals such as
Synthesis, preparation and isolation
Chemical synthesis of Vidarabine was first attained in 1960, as a part of studies on developing potential anticancer agents by B. R. Baker et al.[10] based on unique biological properties of 1-β-D-arabinofuranosyluracil (ara-U).[11] More specifically some of its important reactions include treatments with 2'-deoxyribonucleoside phosphorylase, methyltransferase, or nucleoside phosphorylase, affording the corresponding 5'-phosphate, giving rise to no methylation at its 5-position, or no cleavage of the glycosyl bond in contrast to 5-fluoro-2'-deoxyuridine,.[12] respectively. This earlier work gave impetus to further synthetic studies on the nucleosides with the β-D-arabinofuranosyl moiety including Vidarabine,[13][14][15][16][17][18][19] and the isolation of Vidarabine from the fermentation culture broth of Streptomyces antibioticus.[20]
In addition to the potential anticancer properties antiviral activity of Vidarabine was also demonstrated in 1965.[21][22] Particularly worthy of mention is the collaboration of efficient chemical and enzymatic reactions, i.e., transesterification from ethylene carbonate to uridine accompanied by spontaneous intramolecular elimination of carbon dioxide giving 2,2'-O-anhydro-1-β-D-arabinofuranosyluracil (anhydro-ara-U);[23] and acid-hydrolysis of anhydro-ara-U giving ara-U; and subsequent enzymatic transglycosylation of the sugar moiety of ara-U to the 9-position of adenine with perfect retention of the β-configuration.[24][25][26] and following papers. Ultimately, in 1984, these pioneering syntheses led to the first commercial synthesis of Vidarabine in Japan under the trade name of "Arasena-A." An enzymatic approach duplicating the same concept was also later reported.[27] Furthermore, replacement of adenine with 2-fluoroadenine in the enzymatic transglycosylation reaction from ara-U to the 9-position of adenine made it bring about efficient synthesis of 2-fluoro-9-β-D-arabinofuranosyladenine (fludarabine).[28]
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,[9] however the mechanism of selectivity is not known.
Clinical indication
Vidarabine is an antiviral, active against herpes viruses, poxviruses, rhabdoviruses, hepadnaviruses and some
References
- PMC 3783861.
- ^ ISBN 0-471-89979-8.
- ^ a b Field HJ, De Clercq E (2004). "Antiviral drugs-a short history of their discovery and development" (PDF). Microbiology Today. 31 (2): 58–61.
- ISBN 978-0-12-746642-2.
- ISBN 978-0-443-02094-0.
- ISBN 978-0-911910-10-0.
- ^ a b McGuigan C. Antiviral Chemotherapy. 3rd Year Pharmacy Notes Lecture Notes (Report). Cardiff University.
- PMID 6160811.
- ^ ISBN 978-0-471-27090-4.
- .
- ^ Pizer LI, Cohen SS (1959). Abstract. 136th Meeting, American Chemical Society. pp. 9–C.
- ^ Duschinsky R, Pleven E, Malvica J, Heidelberger C (1957). Abstract. 132nd Meeting, American Chemical Society. pp. 19–C.
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- ^ GB 1159290, "Fermentation of 9-(β-D-Arabinofuranosyl)adenine", published 1969-07-23, assigned to Parke Davis & Company
- S2CID 5231398.
- PMID 5735358.
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- S2CID 25596802.
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- PMID 3521466.
- ^ EP 1464708, Caprioli G, Colombo P, Farina P, Petricciani LA, "A process for the preparation of fludarabine phosphate from 2-fluroroadenine", published 6 October 2004, assigned to Pro Bio Sent Spa
- ^ "Vidarabine". Drug.com.