This document summarizes various anti-viral agents, including nucleoside analogs that inhibit viral DNA polymerase and reverse transcriptase. It discusses idoxuridine, trifluridine, acyclovir and other nucleoside analogs used to treat herpes viruses. It also covers reverse transcriptase inhibitors like zidovudine and didanosine used to treat HIV. Newer agents for HIV include protease inhibitors, entry inhibitors, integrase inhibitors and combination antiretroviral therapy, which is most effective at preventing drug resistance.

1. ANTI-VIRAL
AGENTS
Veronica Jane B. Teo

2. NUCLEOSIDE ANTIMETABOLITES:
INHIBITING VIRAL REPLICATION
INHIBITORS OF DNA POLYMERASE
REVERSE TRANSCRIPTASE
INHIBITORS
MISCELLANEOUS NUCLEOSIDE
ANTIMETABOLITES

3. INHIBITORS OF
DNA
POLYMERASE

4. 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 infected
host cells.
- introduced in 1963 for the
treatment of herpes
simplex keratitis.

5. - 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.

6. 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 that
resist idoxuridine.
- administered topically

7. 3. TRIFLURIDINE
(5-trifluoromethyl-29-deoxyuridine)
VIROPTIC
- a fluorinated pyrimidine
nucleoside that demonstrates in
vitro inhibitory activity against
HSV-1 and HSV-2, CMV, vaccinia
and 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.

8. 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 tumor
viruses.
- 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

9. 5. ADEFOVIR DIPIVOXIL
- active prodrug that is
indicated for the
treatment of chronic
form of hepatitis B

10. 6. ACYCLOVIR
9-[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.

11. 7. VALACYCLOVIR HYDROCHLORIDE
VALTREX
- water-soluble,
crystalline solid
- has been approved in
the treatment of herpes
zoster(shingles) in
immunocompromised
patients

12. 8. GANCICLOVIR
9-[(1,3-dihydroxy-2-propoxy)
methyl]guanine or DHPG
CYTOVENE
- toxicity limits its
therapeutic usefulness to
the treatment and
suppression of sight-
threatening CMV retinitis in
the immunocompromised
patients and to the
prevention of life-
threatening CMV infections
in at-risk transplant
patients.

13. 9. FAMCICLOVIR
- diacetyl prodrug of
pencyclovir

14. 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

15. 11. CIDOFOVIR (S)-3-hydroxy-2-
phosphonomethoxypropyl
cytosine (HPMPC)
VISTIDE
- an acyclonucleotide
analog that possesses
broad-spectrum
activity against
several DNA viruses

16. 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.

17. 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.

18. 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 Prusoff
in 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

19. 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.

20. 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

21. 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.

22. 5. ABACAVIR
- approved for use in
combination therapies
for the treatment of
HIV and AIDS

23. 6. TENEFOVIR DISOPROXIL
- treatment of
HIV infection in
adult patients

24. 7. LAMIVUDINE (-)-2’,3’-dideoxy-3’-thiacytidine,
(-)-b-L-(2R,5S)-1,3-oxathiolanylcytosine, 3TC,
or (-)-(S)-ddC

25. 8. EMTRICITABINE
- orally active NRTI whose
pharmacokinetics are
favorable for once-daily
administration

26. MISCELLANEOUS
NUCLEOSIDE
ANTIMETABOLITES

27. 1. RIBAVIRIN 1-b-D-ribofuranosyl-
1,2,4-thiazole-3-carboxamide
- white, crystalline,
polymorphic solid that
is soluble in water and
chemically stable.

28. 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

29. INTEGRASE INHIBITORS
SHORT-INTERFERING RNA
COMBINATION ANTIVIRAL THERAPY

30. NONNUCLEOSIDE
REVERSE
TRANSCRIPTASE
INHIBITORS

31. 1. NEVIRAPINE (VIRAMUNE)
48% protein bound
2. DELAVIRIDINE (RESCRIPTOR)
98% protein bound
3. EFAVIRENZ (SUSTIVA)
99% protein bound

33. 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.

34. SAQUINAVIR (INVIRASE)
INDINAVIR (CRIXIVAN)
-extensively metabolized by CYP3A4

35. RITONAVIR (NORVIR),
AMPRENAVIR (AGENERASE) AND
NELFINAVIR (VIRACEPT)
-all cause dyslipidemia
and inhibit CYP3A4
-used with at least two
other antiretroviral
agents

36. 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

37. FOSAMPRENAVIR
Used in combination with other HIV drugs in adult
patients.
Prodrug that produces the active drug upon hydrolysis
Administered in combination with RT inhibitors.
TIPRANAVIR
Not a peptidomimetic compound
Drug is administered with a booster dose of ritonavir
Protocol inhibits CYP3A4, causing the levels of
tipranavir to increase

38. HIV ENTRY
INHIBITORS

39. 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.

40. CHEMOKINE
RECEPTOR
BINDERS

41. 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.

42. INHIBITORS OF
GP41 FUSION
ACTIVITY

43. 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.

44. INTEGRASE
INHIBITORS

45. SHORT-
INTERFERING
RNA

46. 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.

47. COMBINATION
ANTIVIRAL
THERAPY

48. 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.

49. 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.

50. THANK YOU
& HAPPY NEW
YEAR
EVERYONE