Nucleoside reverse transcriptase inhibitor Numbering

The identification of the HIV-1-specific non-nucleoside reverse transcriptase inhibitors (NNRTIs) as a separate class of HIV inhibitors was heralded by the discovery of the tetrahydroimidazo[4,5,1 -// .][ 1,4]benzo-diazepin-2(l //)-onc and -thione (TIBO) derivatives (Fig. 7) [58,59] and 1 -(2-hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT) derivatives (Fig. 8) [60,61]. The first TIBO derivatives (R82150, R82913) were the first NNRTIs [58] postulated to act as inhibitors of HIV-1 RT [59], For the HEPT derivatives it became evident that they also interact specifically with HIV-1 RT after a number of derivatives (i.e., E-EPU, E-EBU, and E-EBU-dM) had been synthesized that were more active than HEPT itself [62,63]. Following HEPT and TIBO, several other compounds, i.e., nevirapine, pyridinone, and bis(heteroaryl)piperazine (BHAP), were... 

A number of novel spiro heterocycles, including the triazepinethione 146 have been derived from 3-hydroxy-3-(2-oxocyclohexyl)indolin-2-one 145 by condensation with active methylene compounds <00SC1257>. A condensation process was also used to prepare tricyclic triazepinones related to the non-nucleoside reverse transcriptase inhibitor nevirapine <00JHC1539>. 

Antibodies against the virus but also amantadine and derivatives, interfere with host cell penetration. There are nucleoside analogues such as aciclovir and ganciclovir, which interfere with DNA synthesis, especially of herpes viruses. Others like zidovudine and didanosine, inhibit reverse transcriptase of retroviruses. Recently a number of non-nucleoside reverse transcriptase inhibitors was developed for the treatment of HIV infections. Foscarnet, a pyrophosphate analogue, inhibits both reverse transcriptase and DNA synthesis. Protease inhibitors, also developed for the treatment of HIV infections, are active during the fifth step of virus replication. They prevent viral replication by inhibiting the activity of HIV-1 protease, an enzyme used by the viruses to cleave nascent proteins for final assembly of new vi-rons. 

Amprenavir [am PREN a veer] Like other protease inhibitors, amprenavir is used in combination with a least two nucleoside reverse transcriptase inhibitors. Its long plasma half-life permits twice daily dosing, but the large size and number of capsules per day (16) day may reduce patient compliance. The drug may be less well tolerated than some other protease inhibitors and it is unclear whether amprenavir offers any clinical advantages over other protease inhibitors. 

Given the role of NMR in dmg metabolism smdies, on-hne LC-NMR or LC-NMR-MS is highly attractive [51]. This is demonstrated in a number of applications, e.g., in identification of minary metabolites of acetaminophen [52], and paracetamol [53], and the novel non-nucleoside reverse transcriptase inhibitor GW 420867 [54]. Nowadays, this expensive technique is frequently applied. It is commercially available. 

Telomerase is a multicomponent highly specialized enzyme responsible for the synthesis of telomeres. Its catalytic subunit (TERT, telomerase reverse transcriptase) utilizes the RNA component of the enzyme (TR) as a template to synthesizes telomeric DNA repeats. A number of strategies for telomerase inhibition by low-moleeular dmgs have been proposed. They include the application of nucleoside and non-nucleoside reverse transcriptase inhibitors, antisense oligonucleotides and their analogues against TR RNA, ribozymes and siRNA directed against TR and TERT components of the enzyme, etc. [5-9]. These approaches are rather traditional for the inhibition of enzymes of nucleic acids biosynthesis. Totally different approach is based on the presence of unique stmctural motifs in telomeric DNA called G-quadmplexes (G4). 

Non-nucleoside analogue reverse transcriptase inhibitor Number needed to treat (for benefit, for harm)... 

The oral dose of voriconazole does not have to be adjusted in patients who have renal impairment. However, intravenous administration of voriconazole should be avoided in these patients as the carrier vehicle sulfobu-tyl ether P-cyclodextrin sodium can accumulate in these patients. Dosage adjustment is required in patients who have chronic hepatic impairment. As voriconazole is a substrate for a number of cytochrome P450 enzymes, a number of clinically important dmg interactions occur with dmgs including ciclospotin, tacrolimus, phenytoin, warfarin, HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors. 

Resistance can occur through a number of consequences of viral mutation. There may be reduced phosphorylation of the dmg (for example with nucleoside analogues), alteration of viral enzyme targets (for example with reverse transcriptase inhibitors), or alteration of target channel protein (for example with amantadine). 

The sites at which anti-HIV drugs may. in principle, act, are dealt with in detail under a main heading (see ANTIVIRAL agents). In summary, currently, of the drugs actually in use, a number are reverse transcriptase (enzyme) inhibitors (RTIs). Examples of nucleoside RTIs include zidovudine, didanosine and zalcitabine. Some non-nucleoside RTIs include foscarnet sodium, nevirapine, carbovir and TIBO analogues (some of these are at trial stage only). 

---