Wednesday 4 July 2012

Chapter II: How to kill HIV (HAART)


As promised, now that you have a greater understanding about the mechanism of HIV replication, now its time to explore some ways to counteract it or simply put kill it. Enjoy. ^^


Classes of drugs used in HIV treatment (Highly Active Antiretroviral Therapy)



1.      Nucleoside Analogs (Competitive substrate inhibitor) [1]

AIDS (acquired immunodeficiency syndrome) is caused by infection with the retrovirus HIV (human immunodeficiency virus). A key step in the life cycle of this virus is synthesis of a DNA copy of the viral RNA genome, catalyzed by a reverse transcriptase. Reverse transcriptase is a major target of chemotherapy because it is not essential for normal cells.


AZT (3’-azido-2’,3’-dideoxythymine; Zidovudine) was the first drug approved for treatment of HIV infection. It is a nucleoside analog with an azido group on the sugar. It can be phosphorylated into triphosphate from, which competes with dTTP (deoxythymine triphosphate) for incorporation into the reverse transcript. Once incorporated, it terminates the growing chain of the transcript because the azido group on the 3’ carbon of the sugar is not a substrate for nucleotide addition. AZT is much less efficient at competing with the more accurate cellular DNA polymerases, providing a therapeutic window in which the effect is primarily upon viral replication. (Since the effects of faulty DNA synthesis by AZT affects the virus more efficiently than it does human cells) Nevertheless, side effects include toxicity to bone marrow, which contains rapidly dividing cells, and myopathy that might be related to toxicity to mitochondria, which contain their own DNA polymerase (pol delta). DDI (2’, 3’ dideoxyinosine; didanosine) and dideoxycytidine (zalcitabine) also function as chain terminators after incorporation of their phosphorylated derivatives by the HIV reverse transcriptase.



2.      CCR5 receptor antagonist (Competitive substrate inhibitor) [2]

These are the first antiretroviral drugs which do not target the virus directly. Instead, they bind to the CCR5 receptor on the surface of the T-Cell and block viral attachment to the cell. Most strains of HIV attach to T-Cells using the CCR5 receptor. If HIV cannot attach to the cell, it cannot gain entry to replicate. Currently, three pharmaceutical companies are trying to push through FDA approval with their
small molecule CCR5 antagonist however Maraviroc is the only FDA approved drug as of now.





Putative binding of Maraviroc to the CCR5 receptor



The strongest interaction is estimated to be between maraviroc and glutamic acid (Glu283) through a strong salt-bridge interaction. Types of interaction with CCR5:
* II – T-shaped π-π stacking
* III – parallel displaced interaction
* V – hydrophobic interaction
* VI – limited interaction
* VII – salt-bridge interaction



3.    Reverse transcriptase inhibitor (Non-competitive inhibitors) [3]

Non-nucleoside reverse transcriptase inhibitors inhibit reverse transcriptase by binding to an allosteric site of the enzyme. (Thereby changing its shape and loss of enzymatic activity) Examples of these inhibitors are Efavirenz and Nevirapine.





             4.  Protease inhibitor (Non-competitive inhibitor}

Protease inhibitors (PIs) target viral assembly by inhibiting the activity of protease, an enzyme used by HIV to cleave nascent proteins for the final assembly of new virions. (Thereby resulting in immature HIV that is non-infectious)


       5.  Integrase inhibitor (Non-competitive inhibitor)
Integrase inhibitors inhibit the enzyme integrase, which is responsible for integration of viral DNA into the DNA of the infected cell. There are several integrase inhibitors currently under clinical trial, and raltegravir became the first to receive FDA approval in October 2007.

Reverse transcriptase do not carry out proofreading, thus their error rate is much higher than that of cellular DNA polymerases. This high error rate complicates the treatment of AIDS, because the population of viruses carried by any one patient contains many mutants. Some of these mutants are likely to be resistant to any given therapeutic agent. Thus, many drugs initially reduce the viral load, but later become ineffective due to the selective growth of the viruses in which the drug target is mutated to an insensitive form. Combination therapy, with multiple drugs that target different viral proteins, is an attempt to circumvent this problem.


How reverse transcriptase inhibitor works? (Animation)
How protease inhibitor works? (Animation)

References
[1] Glitz, D.(2006). Textbook of Biochemistry With Clinical Correlations Sixth Edition. Canada: Wiley-Liss.

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