NNRTI interactions NRTIs

How do these NRRIs interact with their final target, the HCV RNA replicase They are phosphorylated to their 5 -triphosphate form, and then inhibit the HCV replicase. As they possess a 3 -hydroxyl function, they may not be considered as obligate chain terminators, but they may act as virtual chain terminators, viz. by steric hindrance exerted by the neighboring 2 -C-methyl and/or 4 -C-azido groups. Similar to their NRTI and NNRTI counterparts in the case of HIV reverse transcriptase, the NRRIs (2 -C-methylnucleosides) interact, upon their phosphorylation to the corresponding 5 -triphosphates, with a region of the HCV RNA replicase (or NS5B RNA-dependent RNA polymerase) that is clearly distinct from the site(s) of interaction of the NNRRIs (Tomei et al. 2005). 

A close-up view showing the relative locations of the commonly identified drug-resistance mutations for NRTIs (in dark-gray) and for NNRTIs (in light-gray) with respect to the bound DNA. Most of the NRTI-resistance mutations are not located at the putative dNTP-binding site, but are at positions to have potential interactions with the nucleic acid template-primer. Conversely, all the NNRTI-re si stance mutations are clustered around the NNIBP and have direct contacts with NNRTIs or have direct effect on... 

At the present time, there are at least 14 compounds that have been formally approved for the treatment of human immunodeficiency virus (HIV) infections. There are six nucleoside reverse transcriptase inhibitors (NRTIs) that, after their intracellular conversion to the 5 -triphosphate form, are able to interfere as competitive inhibitors of the normal substrates (dNTPs). These are zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), and abacavir (ABC). There are three nonnucleoside reverse transcriptase inhibitors (NNRTIs) — nevirapine, delavirdine, and efavirenz — that, as such, directly interact with the reverse transcriptase at a nonsubstrate binding, allosteric site. There are five HIV protease inhibitors (Pis saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) that block the cleavage of precursor to mature HIV proteins, thus impairing the infectivity of the virus particles produced in the presence of these inhibitors. 

D. Efavirenz This NNRTI has been shown to be effective in HIV treatment when used in combination with two NRTIs. Efavirenz is metabolized by hepatic cytochromes P450 and is frequently involved in drug interactions. Toxicity of efavirenz includes CNS dysfunction, skin rash, and elevations of plasma cholesterol. The drug should be avoided in pregnancy since fetal abnormalities have been reported in animals. 

The NNRTis are extensively metabolised by the cytochrome P450 isoenzyme system, particularly by CYP3A4. They are also inducers (nevirapine, efavirenz) or inhibitors (delavirdine) of CYP3A4. NNRTis would therefore be expected to interact with each other, and with protease inhibitors, but not with NRTIs (see below). They also have the potential to interact with other drugs metabolised by CYP3A4, and are affected by CYP3A4 inhibitors and inducers. Delavirdine and efavirenz may also inhibit some other P450 isoenzymes. For a summary, see Table 21.2 , (p.773). 

Lamivudine is cleared predominantly from the body by the kidneys using the organic cationic transport system. Didanosine is not cleared by this mechanism and so is unlikely to interact with lamivudine by this mechanism. Didanosine does not affect the intracellular activation of lamivudine in vitro. In UK and US guidelines, the combination of didanosine with lamivudine is currently a recommended alternative dual NRTI option for use with an NNRTI or a protease inhibitor, for the treatment of HIV-infection in treatment naive patients. 

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