ANTI-VIRAL

AGENTSVeronica Jane B. Teo

NUCLEOSIDE ANTIMETABOLITES:

INHIBITING VIRAL REPLICATION

INHIBITORS OF DNA POLYMERASE

REVERSE TRANSCRIPTASE INHIBITORS

MISCELLANEOUS NUCLEOSIDE ANTIMETABOLITES

INHIBITORS OF

DNA

POLYMERASE

1. IDOXURIDINE (5-iodo-2’-deoxyuridine)

STOXIL and HERPLEX- pale yellow, crystalline solid, soluble in water and alcohol, poorly soluble in most organic solvents, light and heat sensitive.- lacks selectivity, low, sub therapeutic concentrations inhibit the growth of in infectedhost cells.- introduced in 1963 for the treatment of herpes simplex keratitis.

- outside the United States, a solution of idoxuridine in dimethyl sulfoxide is available for the treatment of herpes labialis, genitalis and zoster.

- 0.1% ophthalmic solution and 0.5% ophthalmic ointment.

2. CYTARABINE

- pyrimidine nucleoside drug- primarily used as an

anticancer agent for Burkitt lymphoma and myeloid and lymphatic leukemias.

- antiviral use in the treatment of herpes zoster(shingles), herpetic keratitis and viral infections thatresist idoxuridine.

- administered topically

3. TRIFLURIDINE(5-trifluoromethyl-29-deoxyuridine)

VIROPTIC- a fluorinated pyrimidine nucleoside that demonstrates in vitro inhibitory activity against HSV-1 and HSV-2, CMV, vacciniaand some adenoviruses. - approved in the United States for treatment of primary keratoconjunctivitis and recurrent epithelial keratitis caused by HSV types 1 and 2.- solutions of this drug are heat sensitive and require refrigeration.

4. VIDARABINE(9-B-D-arabinofuranosyladenine)

VIRA-A- white, crystalline monohydrate, soluble in water- introduced in 1960 as an anticancer agent- it is active against herpesviruses, poxviruses, rhabdoviruses, hepadnavirus, and some RNA tumorviruses.- marketed in 1977 as an alternative to idoxuridine for the treatment of HSV keratitis and HSV encephalitis- now obtained by fermentation with strains of Steptomyces antibioticus

5. ADEFOVIR DIPIVOXIL

- active prodrug that is indicated for the treatment of chronic form of hepatitis B

6. ACYCLOVIR9-[2-(hydroxyethoxy)methyl]-9H-guanine

ZOVIRAX- chemically stable, white, crystalline solid, slightly soluble in water.- most active against HSV type 1, about two times less against HSV type 2, and 10 times less potent against varicella-zoster virus (VZV)- comes in oral and parenteral- oral preparation is used in the initial treatment of genital herpes and to control mild recurrent episodes. Also for short-term treatment of shingles and chickenpox caused by VZV.

7. VALACYCLOVIR HYDROCHLORIDE

VALTREX- water-soluble, crystalline solid- has been approved in the treatment of herpes zoster(shingles) in immunocompromisedpatients

8. GANCICLOVIR9-[(1,3-dihydroxy-2-propoxy) methyl]guanine or DHPGCYTOVENE- toxicity limits its therapeutic usefulness to the treatment and suppression of sight-threatening CMV retinitis in the immunocompromisedpatients and to the prevention of life-threatening CMV infections in at-risk transplant patients.

9. FAMCICLOVIR

- diacetyl prodrug of pencyclovir

10. PENCYCLOVIR 9-[4-hydroxy-3-hydroxymethyl]but-1-y1] guanine

- topical treatment of recurrent herpes labialis (cold sores) in adults. - it is effective against HSV-1 and HSV-2

11. CIDOFOVIR (S)-3-hydroxy-2-phosphonomethoxypropyl cytosine (HPMPC)

VISTIDE- an acyclonucleotideanalog that possesses broad-spectrum activity against several DNA viruses

12. FOSCARNET SODIUM

FOSCAVIR- second-line drug for the treatment of retinitis caused by CMV in patients with AIDS- nephrotoxicity is common- hypocalcemia, hypomagnesemia, hypokalemia, and hypophosphatemia are observed in patients treated with foscarnet- it is available as a sterile solution intended for slow intravenous infusion.

REVERSE

TRANSCRIPTASE

INHIBITORS

A genomic RNA from the virus is converted into a cDNA-RNA complex, then into double-stranded DNA ready for integration into the host chromosome.

1. ZIDOVUDINE (3’-azido-3’-deoxythymidine or AZT)

- analog of thymidine that possesses antiviral activity against HIV-1, HIV-2, HTLV-1 and several other retroviruses. - synthesized by Lin and Prusoffin 1978 as an intermediate in the preparation of amino acid analogs of thymidine.- recommended for the management of adult patients with symptomatic HIV infection (AIDS or ARC) who have a history of confirmed Pneumocystis carinii pneumonia

2. DIDANOSINE 2’,3’-dideoxyinosine (ddI)

VIDEX- recommended for the treatment of patients with advanced HIV infection who have received prolonged treatment with AZT but have become intolerant to, or experienced immunosuppression from, the drug.- AZT and ddI act synergistically to inhibit HIV replication in vitro, and ddI is effective against some AZT-resistant strains of HIV.

3. ZALCITABINE (2’,3’-dideoxycytidine

or ddCyd)

- approved for the treatment of HIV infection in adults with advanced disease who are intolerant to AZT or who have disease progression while receiving AZT.- Ddc is combined with AZT for the treatment of advanced HIV infection

4. STAVUDINE 2’,3’-didehydro-2’-

deoxythymidine

ZERIT- acid stable and well absorbed (about 90%) following oral administration- available as capsules for oral administration- recommended for the treatment of adults with advanced HIV infection who are intolerant of other approved therapies who have experienced clinical or immunological deterioration while receiving these therapies.

5. ABACAVIR

- approved for use in combination therapies for the treatment of HIV and AIDS

6. TENEFOVIR DISOPROXIL

- treatment of HIV infection in adult patients

7. LAMIVUDINE (-)-2’,3’-dideoxy-3’-thiacytidine,

(-)-b-L-(2R,5S)-1,3-oxathiolanylcytosine, 3TC,

or (-)-(S)-ddC

8. EMTRICITABINE

- orally active NRTI whose pharmacokinetics are favorable for once-daily administration

MISCELLANEOUS

NUCLEOSIDE

ANTIMETABOLITES

1. RIBAVIRIN 1-b-D-ribofuranosyl-

1,2,4-thiazole-3-carboxamide

- white, crystalline, polymorphic solid that is soluble in water and chemically stable.

NEWER AGENTS FOR THE

TREATMENT OF HIV INFECTION

NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

HIV PROTEASE INHIBITORS

HIV ENTRY INHIBITORS

CHEMOKINE RECEPTOR BINDERS

INHIBITORS OF GP41 FUSION ACTIVITY

INTEGRASE INHIBITORS

SHORT-INTERFERING RNA

COMBINATION ANTIVIRAL THERAPY

NONNUCLEOSIDE

REVERSE

TRANSCRIPTASE

INHIBITORS

1. NEVIRAPINE (VIRAMUNE)

48% protein bound

2. DELAVIRIDINE (RESCRIPTOR)

98% protein bound

3. EFAVIRENZ (SUSTIVA)

99% protein bound

HIV PROTEASE INHIBITORS

HIV protease is an enzyme that cleaves gag-pro propeptides to yield active enzymes that function in the maturation and propagation of new virus.

SAQUINAVIR (INVIRASE)

INDINAVIR (CRIXIVAN)-extensively metabolized by CYP3A4

RITONAVIR (NORVIR), AMPRENAVIR (AGENERASE) AND NELFINAVIR (VIRACEPT)

-all cause dyslipidemiaand inhibit CYP3A4-used with at least two other antiretroviral agents

LOPINAVIR-protease inhibitor that has been approved for

use in combination with ritonavir for patients with HIV who have not responded to other treatment modalities.

ATAZANAVIR-antiretroviral agent that has been approved by the FDA for use in combination with other anti-RT agents for the treatment of HIV infections

FOSAMPRENAVIRUsed in combination with other HIV drugs in adult patients. Prodrug that produces the active drug upon hydrolysisAdministered in combination with RT inhibitors.

TIPRANAVIRNot a peptidomimetic compoundDrug is administered with a booster dose of ritonavirProtocol inhibits CYP3A4, causing the levels of tipranavir to increase

HIV ENTRY

INHIBITORS

Entry of HIV into a cell is a complex process that involves several specific membrane protein interactions.

glycoprotein gp120

Protein gp41- acts as the anchor for gp120 in the virus.

CHEMOKINE

RECEPTOR

BINDERS

Bicyclam compound AMD-3100 was the first compound identifies as a CXCR4-specific inhibitor that interferes with the replication of X4 but not R5 viruses.

INHIBITORS OF

GP41 FUSION

ACTIVITY

The fusion of the HIV-1 viral envelope with host plasma membrane is mediated by gp41, a transmembrane subunit of the HIV-1 glycoprotein subunit complex.

Pentafuside (T-20) is a 36-mer peptide that is derived from the C-terminal repeat of gp41.

Pentafuside is a potent inhibitor of HIV-1 clinical isolates, and it is currently in clinical trials.

INTEGRASE

INHIBITORS

SHORT-

INTERFERING

RNA

RNA interference is a phenomenon that has been recently used as a way to silence genes that are part of viral replication cycles.

The siRNAs are found in higher organisms (eukaryotes) and are typically double-stranded duplexes of RNA of about 21 base pairs. The siRNAs instruct the cell to split specific mrRNAs that have identical sequences as the siRNAs. As antiviral therapy, the idea would be for the siRNAs to stop synthesis of mRNAs of a pathogenic organism.

COMBINATION

ANTIVIRAL

THERAPY

The antiviral effect of the combination is excellent, toxicities are decreased, and resistance to any drug in the combination is slow to develop. Resistance to single drugs such as amantadine, ganciclovir, and acyclovir is problematic. Administered of a given agent in combination with other types of drugs retards the development of such resistance. Combination treatment is especially important in antiretroviral therapy.

Typical antiretroviral therapy, as exemplified by HIV treatment, includes combinations of NRTI or NNRTI along with PIs. The key that makes the combination work is that the drugs act to inhibit HIV virus replication at different stages of the viral infective cycle. The RT inhibitors (NRTIs or NNRTIs) prevent RNA formation or viral protein synthesis or inactivate the catalytic site of RT (NNRTIs). The PIs act once the provirus integrates into the host’s genes. Protease is necessary to split viral precursor polypeptides into new virus. The combination of RTs and PIs is synergistc.

THANK YOU

& HAPPY NEW

YEAR

EVERYONE