Nucleosides infection of HSV than the recurrent ones.

Nucleosides contain a sugar linked to a nitrogen-containing base. Purines and pyrimidines are important bases that have ring structures which are bound to ribose or 2-deoxyribose to complete the nucleoside. A nucleotide is formed when inorganic phosphate is added to the nucleoside.There are many drugs which are analogs of Nucleoside & Nucleotides such as antivirals, antimicrobial and cytotoxic agents, some of them will be discussed.

     * Acyclovir * Is a drug analog of guanine nucleoside which lacks the 2? and 3? site.a prototype of antiviral agents, in which viral kinase and host cell enzymes phosphorylate it intracellularly to become inhibitors of viral DNA synthesis.  À   Mechanism of action:Viral DNA synthesis inhibition upon interaction with HSV thymidine kinase (HSV TK) & DNA polymerase.It penetrates the cell which is infected with the virus and its phosphorylation occur initially with HSV TK.Conversion of the monophosphate to acyclovir triphosphate occurs by cellular enzymes, which competes for endogenous dGTP.

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The immunosuppressive agent mycophenolate mofetil potentiates the antiherpes activity through depleting intracellular dGTP pools.Acyclovir triphosphate competitively inhibits viral DNA polymerases as well as it also is incorporated into viral DNA, because it lacks 3?-hydroxyl group it acts as a chain terminator.Irreversible inactivation result from “suicide inactivation” mechanism in which terminated DNA template containing acyclovir binds the viral DNA polymerase.    À   Therapeutic Uses:HSV-1, HSV-2, VZV, and EBV are all of which Acyclovir is active against while It’s least active against CMV and’s more beneficial in initial infection of HSV than the recurrent ones.For the immunocompromised patients who experience both more frequent and severe HSV and VZV infections, Because VZV is less susceptible to acyclovir than HSV, higher doses are used.

Administration of systemic corticosteroid along with Oral acyclovir beneficial in treating Bell palsy.Intravenous administration for severe herpes disease, including encephalitis, and for neonatal HSV infection. Parenteral administration result in toxic effects of include delirium, tremor, seizures, hypotension, and nephrotoxicity* Zidovudine *Zidovudine the first antiretroviral agent to be approved and it is a synthetic thymidine analog which is marketed in oral tablets, capsules, and solution as well as a solution for intravenous injection and also available in co-formulated tablets with lamivudine or with lamivudine and abacavir.

             À   Mechanism of action:Intracellular zidovudine is phosphorylated to zidovudine 5?-triphosphate, because it is incorporated by reverse transcriptase into nascent DNA but lacks a 3?-hydroxyl group it terminates the elongation of proviral DNA.Cellular Thymidylate kinase is competitively inhibited by monophosphate, reducing the amount of intracellular thymidine triphosphate. Zidovudine-triphosphate only weakly inhibits cellular DNA polymerase ? but appears to be a more potent inhibitor of mitochondrial polymerase ?.Due to the inefficient conversion of zidovudine-monophosphate to diphosphate, high concentrations of the monophosphate accumulate intracellularly and serve as a precursor for the formation of triphosphate.    ‘ À   Therapeutic use: Zidovudine active against HIV-1 & HIV-2. It is active in lymphoblastic and monocytic cell lines but of no impact on HIV infected cells, and appears to be more active inactivated than in resting lymphocytes because of thymidine kinase.

FDA has approved it for the treatment of adults and children with HIV infection and for preventing vertical transmission.         * Trifluridine *  Trifluridine is a fluorinated pyrimidine nucleoside. À   Mechanism of action:In vitro inhibitory activity against HSV types 1 and 2, CMV, and vaccinia. It inhibits replication of herpesviruses, including acyclovir-resistant strains, and cellular DNA synthesis at relatively low concentrations.

Trifluridine monophosphate inhibits thymidylate synthase irreversibly, and Trifluridine triphosphate is a competitive inhibitor of thymidine triphosphate incorporation into DNA; Trifluridine is incorporated into viral and cellular DNA. À   Therapeutic use: Trifluridine used for the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis owing to HSV types 1 and 2.The topical form is more active than idoxuridine in HSV ocular infections, it also appears to be effective in some patients with acyclovir-resistant HSV cutaneous infections.

* Cytarabine *Cytarabine is an analog of pyrimidine nucleoside that is used as an antimetabolite antineoplastic agent that inhibits the synthesis of DNA.  À   Mechanism of action:Cytarabine is an antimetabolite analogue of cytidine with a modified sugar moiety (arabinose instead of ribose). It’s converted into triphosphate and competes with cytidine for the incorporation into the DNA.

DNA replication is stopped during the S phase of the cell cycle, because the arabinose sugar sterically hinders the rotation of the molecule within DNA.Cytarabine inhibits DNA polymerase as well, leading to decrease the DNA replication and repair.  À   Therapeutic use: Cytarabine is an antineoplastic agent use for the treatment of deferent types of leukemia such as: acute and chronic myeloid leukemia (AML and CML), acute promyelocytic leukemia (APL) and acute lymphocytic leukemia (ALL).Cytarabine can also be used for the treatment of different type of lymphoma like Hodgkin’s lymphoma. * Didanosine *Didanosine (2?, 3?-dideoxyinosine) is an analogue of purine nucleoside that is active against HIV-1, HIV-2, and other retroviruses, including HTLV-1.  À   Mechanism of action:Didanosine enters the cells via a nucleoside transporter then undergoes several phosphorylation reaction by cellular enzymes to form Triphosphate, which is an active anabolite that functions as an antiviral adenosine analogue.

Didanosine is incorporated by reverse transcriptase into nascent HIV DNA but lacks a 3?-hydroxyl group, and so it cuts out the elongation of proviral DNA. À   Therapeutic use: Didanosine is approved to be use for the treatment of HIV infection in children and adult combined with other antiretroviral agentsDidanosine has long-term efficacy when combined with other nucleoside analogs and HIV protease inhibitors, also has beneficial effects in the treatment of infants and children’s However, Didanosine is no longer widely prescribed, because there is a lot of other agents with less toxicity nowadays.  * Conclusion *In summary, a lot of drugs have been developed based on nucleoside and nucleotides many of them are of immense value and many of them have side effects.


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