2. Viral Resistance to Aciclovir
Aciclovir-resistant strains of herpes are appearing.
This occurs when mutations of the viral thymidine kinase result in an enzyme which no longer phosphorylates aciclovir.
Or when the viral DNA polymerase mutates to a form that no longer recognizes the activated drug.

3. Prodrugs of Aciclovir
Aciclovir itself is polar, and thus the oral bioavailability is low.
A valine ester of aciclovir, known as valaciclovir, is more bioavailable. This ester is cleaved by esterases.
Also, the C6 oxygen can be removed to produce desciclovir, also a prodrug, which is converted to aciclovir by xanthine oxidase.

4. Families of herpesviruses
Aciclovir is effective against the a-subfamily of herpesviruses, but not against the b-subfamily.
However, other drugs, such as ganciclovir, which has an additional hydroxyl group, thus resembling the natural substrate a bit more closely.

5. Ganciclovir is phosphorylated by thymidine kinases produced by both the - and the -subfamilies of herpes viruses.
Thus ganciclovir can be used to treat cytomegalovirus (CMV) infections
Cytomegalovirus is a common virus that infects most people worldwide. CMV infection is usually harmless and a healthy immune system can hold the virus in check. However, if a person's immune system is seriously weakened, the virus can become active and cause CMV disease.
A less polar analog is valganciclovir, which is a valine ester at one of the hydroxyl groups.

6. Penciclovir
Famcyclovir (Famvir)
Other modifications include substituting the ether oxygen with a methylene (CH2) to produce penciclovir and famciclovir (diacetate ester of penciclovir)
These drugs are used topically for the treatment of cold sores and intravenously for the treatment of HSV in immunocompromised indivuals.

7. Deoxycytidine monophosphate Cidofovir
Some viruses are immune from the action of this class of antiviral agents, due to their lack of the thymidine kinase enzyme.
The agent cidofovir (shown above) was designed to overcome this problem by incorporating an appropriately placed phosphonomethylene group to mimic the phosphate of deoxycytidine monophosphate.
However, with the added phosphono group, the drug is extremely polar and has low oral bioavailability.

8. The three nucleoside analogs shown above are mistaken for the structurally related nucleosides.
These compounds appear to inhibit viral DNA polymerase.
Foscarnet is used to treat ganciclovir-resistant CMV or to treat aciclovir-resistant HSV. It has renal toxicity.
Foscarnet it a non-competitive inhibitor of viral DNA polymerase.

9. HIV HIV = Human Immuno-deficiency Virus
HIV is an RNA virus which contains two identical strands of (+)ssRNA in its capsid.
HIV is a retrovirus (i.e. viral RNS serves as template for the synthesis of a complementary DNA)
HIV infection usually progresses to AIDS
AIDS = Acquired Immunodeficiency Syndrome.
This stage of HIV infection is usually characterized by opportunistic diseases, including Pneumocystis carinii pneumonia, Kaposi sarcoma, cytomegalovirus disease, etc.

10. HIV Introduction
HIV-1 is responsible for AIDS in America, Europe, and Asia
HIV-2 occurs mainly in western Africa
At present, anti-HIV drugs are aimed at two targets: reverse transcriptase and HIV protease.

11. Good animation of HIV-1 Lifecycle:

12. Introduction to HIV treatment: Resistance

13. HIV Lifecycle and Opportunities for New Therapeutic Agents

14. Treatment of HIV
When HIV replicates (makes new copies of itself) it often makes mistakes.
Taking two or more antiretrovirals at the same time vastly reduces the rate at which resistance develops
The term Highly Active Antiretroviral Therapy (HAART) is used to describe a combination of three or more anti-HIV drugs.

15. Treatment of HIV Current classes of antiretroviral drugs include:
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors
Non-Nucleoside Reverse Transcriptase Inhibitors
Protease Inhibitors
Fusion or Entry Inhibitors
Integrase Inhibitors

16. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors
These were the first type of drug available to treat HIV infection in 1987.
NRTIs (also known as nucleoside analogues or nukes) interfere with the action of an HIV protein called reverse transcriptase, which the virus needs to make new copies of itself.
NRTIs are sometimes called the "backbone" of combination therapy because most regimens contain at least two of these drugs.

17. zidovudine/Retrovir(AZT, ZDV) didanosine/Videx, Videx EC (ddI)
Antiretroviral Agents Currently Available (generic name/Trade name) Nucleoside Analogs (NRTI’s)
zidovudine/Retrovir(AZT, ZDV)
didanosine/Videx, Videx EC (ddI)
zalcitabine/HIVID (ddC)
stavudine/Zerit (d4T)
lamivudine/Epivir (3TC)
abacavir/Ziagen (ABC)

18. Nucleoside Reverse Transcriptase Inhibitors (NRTI’s)
didanosine/Videx, Videx EC (ddI)
zalcitabine/HIVID (ddC)
Zidovudine/Retrovir
(AZT, ZDV)

19. Nucleoside Reverse Transcriptase Inhibitors (NRTI’s)
Stavudine/Zerit (d4T)
Lamivudine/Epivir
(3TC)
Abacavir/Ziagen (ABC)

20. Nucleoside Reverse Transcriptase Inhibitors (NRTI’s)

21. Nucleotide Reverse Transcriptase Inhibitor
Tenofovir disoproxil fumarate

22. Animation of action of AZT

23. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI’s)
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), started to be approved in 1997.
Like the nukes, NNRTIs (also known as non-nucleosides or non-nukes) stop HIV from replicating within cells by inhibiting the reverse transcriptase protein.

24. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI’s)
nevirapine/Viramune (NVP)
delavirdine/Rescriptor (DLV)
efavirenz/Sustiva (EFV)
NNRTI’s are generally hydrophobic molecules that bind to an allosteric binding site
Binding to this allosteric site locks the neighboring substrate-binding site into an inactive conformation.
However, resistance to NNRTI’s can develop rapidly, and thus they are used in combination with NRTI’s

25. Non-nucleoside reverse transcriptase inhibitors

26. Protease Inhibitors indinavir/Crixivan ritonavir/Norvirs
aquinavir/Invirase, Fortovase
nelfinavir/Viracept
amprenavir/Ageneras
elopinavir/ritonavir, Kaletra

27. Chemical Mechanism of HIV Protease Hydrolysis

28. Modeling an inhibitor after the transition state may result in a tighter-binding inhibitor
But the actual transition state (in box above) is chemically unstable, so a number of more stable “transition state isosteres” have been devised.

29. HIV Protease Inhibitors
Indinavir/Crixivan
Ritonavir/Norvirs
Nelfinavir/Viracept

30. Development of saquinavir

31. Tipranavir
Tipranavir, or tipranavir disodium, is a nonpeptidic protease inhibitor (PI) manufactured by Boehringer-Ingelheim under the trade names Aptivus®. It is administered with ritonavir in combination therapy to treat HIV infection and is given as two 250mg capsules together with 200mg of ritonavir twice daily.

32. Tipranvir
Tipranavir has the ability to inhibit the replication of viruses that are resistant to other protease inhibitors and it recommended for patients who are resistant to other treatments. Resistance to tipranavir itself seems to require multiple mutations.

33. Animation of tipranavir, a new HIV protease inhibitor

34. Fusion or Entry Inhibitors
Entry inhibitors prevent HIV from entering human immune cells.
There are several key proteins involved in the HIV entry process:
CD4, a protein receptor found on the surface of Helper T cells in the human immune system, also called CD4+ T cells
gp120, a protein on HIV surface that binds to the CD4 receptor
CCR5, a second receptor found on the surface of CD4+ cells, called a chemokine coreceptor
CXCR4, another chemokine coreceptor found on CD4+ cells
gp41, a HIV protein, closely associated with gp120, that penetrates the cell membrane

35. Approved Entry Inhibitors
Maraviroc (brand-named Selzentry, or Celsentri outside the U.S.)
Enfuvirtide (INN) is an HIV fusion inhibitor, It is marketed under the trade name Fuzeon (Roche).

36. Maraviroc
Approved in April, 2007 and marketed by Pfizer

37. Maraviroc Maraviroc is an entry inhibitor.
Specifically, maraviroc blocks the chemokine receptor CCR5 which HIV uses as a coreceptor to bind and enter a human helper T cell.
Because HIV can also use another coreceptor, CXCR4, an HIV tropism test such as a trofile assay must be performed to determine if the drug will be effective.

38. Enfuvirtide (Fuzeon)
This drug is a small peptide of the following sequence: Acetyl-YTSLIHSLIEESQNQ QEKNEQELLELDKWASLWNWF-amide
By virtue of its peptide nature, enfuvirtide is marketed in injectable form. The lyophilised enfuvirtide powder must be reconstituted by the patient and administered twice daily by subcutaneous injection

39. Enfuvirtide (Fuzeon)
Enfuvirtide therapy costs an estimated $25,000 per year in the United States.
Its cost and inconvenient dosing regimen are factors behind its use as a reserve, for "salvage" therapy in patients with multi-drug resistant HIV.

40. Approved HIV Integrase Inhibitor
Raltegravir (MK-0518, brand name IsentressTM) is an antiretroviral drug produced by Merck & Co, used to treat HIV infection.
It received FDA approval in October 2007, the first of a new class of HIV drugs, the integrase inhibitors, to receive such approval.

41. Raltegravir
Raltegravir is approved only for use only in individuals whose infection has proven resistant to other HAART drugs.
As with any HAART medication, raltegravir is unlikely to show durability if used as monotherapy.
Raltegravir is taken orally twice daily.