How Antiretroviral Drugs Work

A nucleotide is an organic molecule consisting of a base, a sugar, and phosphate.

A nucleoside is similar, except it does not contain a phosphate.

Nucleotides linked together in a strand form a nucleic acid.
The most common nucleic acids are ribonucleic acid (RNA) and deoxyribonucleic acid (DNA).

• RNA is a chain of nucleotides, each composed of ribose (a five carbon sugar) + nitrogenous base (adenine, guanosine, cytosine or uracil) + phosphate.
• DNA is a double strand of nucleotides, each composed of deoxyribose (a five carbon sugar) + nitrogenous base (adenine, guanosine, cytosine or thymine) + phosphate.

DNA stores the instructions required for eukaryotic cellular reproduction, development and function. RNA is transcribed from the genes encoded in the DNA. Transcribed RNA forms a template upon which protein synthesis occurs. Cells respond to stimulus that cause DNA to transcribed a specific RNA template. The RNA translates a protein which produces the required cellular activity.

HIV belongs to a group of viruses called retrovirus. A retrovirus has genes comprised of RNA. Like all viruses, HIV "replicates" or "copies itself" within host cells. HIV is classified as a retrovirus because it uses the enzyme reverse transcriptase to transcribes its RNA genes to form a double stranded DNA segment. The viral enzyme integrase inserts the viral DNA into the host cell genome, completing the infection. Once embedded in the genome, viral DNA transcribes viral RNA. The viral RNA uses the host cell to produce viral components that will be assembled into a multitude of virion.

Antiretroviral (ARV) drugs inhibit the replication of HIV at various stages of its life cycle. Classes of approved ARV drugs include:

1. Nucleoside reverse transcriptase inhibitors (NRTIs), interfere with the production of viral DNA by substituting a synthetic nucleotide that has been intentionally created to block the addition of a subsequent nucleotide. When an NRTI is added to the viral DNA chain it leads to a termination of viral DNA transcription.
2. Protease inhibitors (PIs), interfere with the maturation of HIV by preventing the cleavage of long protein strands into functional HIV components.
3. Non-nucleoside reverse transcription inhibitors (NNRTIs) work by binding to and altering the structure of the reverse transcriptase enzyme, so that it is unable to function properly.
4. Fusion inhibitors currently being developed bind to the transmembrane protein gp41. Binding prohibits a gp41 conformational change necessary to fuse the virus to the target cell.
5. Entry inhibitors Maraviroc (Selzentry®) is the first of a new class of medications targeting the CCR5 coreceptor on the CD4+ T-cell. Maraviroc binds to the CCR5 coreceptor stopping CCR5 tropic HIV-1 from securely attaching to the CD4+ T-cell.
6. Integrase inhibitors block the ability of the HIV enzyme integrase from splicing the HIV DNA strand into the host cell genome.
7. Post-attachment inhibitor (Ibalizumab-uiyk) binds to the CD4 protein and interferes with drawing HIV-1 virus close enough to the host cell membrane to allow viral/host membrane fusion.
8. CAPSID Inhibitors are a new class of drugs for treating HIV-1. Capsid inhibitors work attaching to the HIV-1 virus’ protein shell (the capsid), thereby interfering with multiple essential steps of the viral lifecycle. Lenacapavir was FDA-approved in 2022.
   

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