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nukes non-nukes and tides
May 28, 2001

Can you explain, in simple terms, the differences between nukes, non-nukes, and nucleotide reverse transcriptase inhibitors and the mechanisms they use to stop viral replication?

Response from Dr. Young

HIV reverse transcriptase is the viral enzyme that is largely responsible for replication of the viral genes. There are three different classes of medications that inhibit the HIV reverse transcriptase.

Nucleoside RT inhibitors (nukes) are the largest class of drugs (ZDV, 3TC, d4T, ddI, ddC, abacavir). These drugs have to be activated before they can inhibit the virus. Cellular enzymes convert the drugs into a phosphorylated form called nucleotides. One investigational drug, tenofovir, comes as a phosphorylated form and as such is a nucleotide. These drugs compete with the natural substrate of RT (naturally occuring nucleotides) for binding to the active site of RT and when incorporated into the growing viral genome, prevent further addition of nucleotides.

Non-nucleosides (delaviradine, efavirenz, nevirapine) bind to a site in RT that is separate from the nukes and nucleotides. They inhibit the enzyme in a non-competitive fashion, since they don't compete with a natural substrate. By binding, the non-nukes alter the behavior of the RT, inhibiting it's normal replication function.



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