Nucleotide RT inhibitors

The 2, 3 -dideoxynucleoside (ddN) analogues (Fig. 3) encompass a vast group of compounds that have been found active against HIV and HBV, although they have been primarily pursued for the treatment of HIV infections (AIDS). They are targeted at the HIV-associated reverse transcriptase (RT) and therefore also referred to as nucleoside reverse transcriptase inhibitors (NRTIs). They have to be distinguished from the nucleotide reverse transcriptase inhibitors (NtRTIs) such as adefovir (PMEA) and tenofovir (PMPA) (see above) which, like the NRTIs, act as chain... 

There are also now a number of non-nucleotide reverse transcriptase inhibitors and the most useful of these are nevirapine (Viramune, 1996) and delaviridine (Rescriptor, 1997), which appear to act at an allosteric site close to the active site of RT. This means that they block the subtle (and apparently essential) changes in the three-dimensional structure that occur when nucleotide substrates bind to the active site of RT. 

An example of a potent noncompetitive inhibitor of HIV-RT is the drug nevirapine, a benzodiazepine analogue (16), which is extremely tight-binding to the enzyme, having a /<, in the nanomolar range. As can be seen in the structure of nevirapine, the drug bears no resemblance to any of the natural nucleotide... 

RT). This viral protein is the target of narrow spectrum but rather specific inhibitors with reduced toxicity profiles. Nucleoside reverse transcriptase inhibitors (NRTls) are nucleoside analogues competing with the natural substrate of RT. Three consecutive phosphorylations are required for the activity of NRTls, but the first is generally considered as the most difficult and prompted the development of mono-phosphorylated analogues (i.e. nucleotide derivatives). If phosphate and phosphonate derivatives are well represented, the phosphinates are still rarely encountered as phosphate surrogate in this series. 

In parallel, non-nucleoside reverse transcriptase inhibitors (NNRTIs) inhibit RT by a non-competitive binding to an allosteric site closely located to the catalytic site [18]. The short distances separating the allosteric and the binding sites suggest that NNRTIs alter the function of RT and directly disturb the interactions between the nucleotide natural substrates and the active site. 

Sofia MJ, Chang W, Furman PA, Mosley RT, Ross BS (2012) Nucleoside, nucleotide, and non-nucleoside inhibitors of hepatitis C virus NS5B RNA-dependent RNA-polymerase. J Med Chem 55 2481-2531... 

Unanticipated by Crick was the existence of an enz3ane capable of copying RNA into DNA - reverse transcriptase. HIV reverse transcriptase (RT) copies the HIV genomic RNA into a DNA duplex which is subsequently inserted into the human host s DNA. HTV RT is the target of many anti-AIDS drugs, including AZT and many non-nucleotide inhibitors such as nevirapine. 

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