1. HIV = Human Immunodeficiency 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

2. AIDS = Acquired Immunodeficiency Syndrome.
This stage of HIV infection is usually characterized by opportunistic diseases, including Pneumocystis carinii pneumonia, Kaposi sarcoma, cytomegalovirus disease, etc.

4. 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.

6. Good animation of HIV-1 Lifecycle:
Link

10. Introduction to HIV treatment: Resistance

11. HIV Lifecycle and Opportunities for New Therapeutic Agents

12. 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.

13. 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

14. 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.

15. 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)

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

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

18. Nucleoside Reverse Transcriptase Inhibitors (NRTI’s)

19. Nucleotide Reverse Transcriptase Inhibitor
Tenofovir disoproxil fumarate

20. Mechanism of action of AZT
Link

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

22. 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
Link

25. Non-nucleoside reverse transcriptase inhibitors

28. Efavirenz (Sustiva)

30. Delavirdine
(Rescriptor)

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

32. Chemical Mechanism of HIV Protease Hydrolysis
Link

33. 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.

34. HIV Protease Inhibitors
Indinavir/Crixivan

35. HIV Protease Inhibitors
Ritonavir/Norvir

36. HIV Protease Inhibitors
Nelfinavir/Viracept

38. Amprenavir
(Agenerase)

39. Lopinavir
Ritonavir

40. Development of saquinavir

41. 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.

42. 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.

43. Animation of tipranavir, a new HIV protease inhibitor

47. 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

48. Link

49. 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).

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

51. Maraviroc (Selzentry)
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.

52. Enfuvirtide (Fuzeon)
This drug is a small peptide of the following sequence: Acetyl-YTSLIHSLIEESQNQ QEKNEQELLELDKWASLWNWF-amide

54. 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

55. 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.

56. 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.

57. Raltegravir (Isentress)
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.

59. Assigned Reading
An Introduction to Medicinal Chemistry by Graham L. Patrick, pp

60. Homework Questions
Draw the structure of AZT and discuss how the nucleoside reverse transcriptase inhibitors (NRTIs) interfere with DNA synthesis. Structurally, what must happen to these molecules before they can perform their function?
Show the stepwise mechanism for the hydrolysis of a peptide bond catalyzed by an aspartyl protease (such as HIV protease) using arrows to depict the movement of electrons.
Draw the structure of saquinavir, the first HIV protease inhibitor on the market, and discuss how/why this inhibitor is effective against this viral enzyme.