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Non-nucleoside reverse transcriptase
In 2008, 25 years after the human immunode\ufb01ciency virus (HIV) was discovered as the then tenta- tive aetiological agent of acquired immune de\ufb01ciency syndrome(AIDS), exactly25anti-HIVcompounds have been formally approved for clinical use in the treatment of AIDS. These compounds fall into six categories: nucleoside reverse transcriptase inhibitors (NRTIs: zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and emtricitabine); nucleotide reverse transcriptase inhibitors (NtRTIs: tenofovir); non-nucleoside reverse transcriptase inhibitors (NNRTIs: nevirapine, delavirdine, efavirenz and etravirine); protease inhibitors (PIs: saquinavir, ritonavir, indinavir, nel\ufb01navir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir and darunavir); cell entry inhibitors [fusion inhibitors (FIs: enfu- virtide) and co-receptor inhibitors (CRIs: maraviroc)]; and integrase inhibitors (INIs: raltegravir). These compounds should be used in drugcombinationregimens to achieve the highest possible bene\ufb01t, toler- ability andcompliance andto diminish the riskof resistance development.
Within 2 years after acquired immune de\ufb01ciency syndrome (AIDS) hadbeen identi\ufb01ed as a disease in1981, human immunode- \ufb01ciencyvirus (HIV) [originally called lymphadenopathy-associated virus (LAV) and human T-lymphotropic virus type III (HTLV-III), HTLV-I and -II being humanT-leukaemicviruses type1 and2][1,2]
was isolated as the putative cause of the disease. This launched an intensive searchfor compounds that would inhibit infectivity and replication of the virus and, hopefully, favourably alter the course of the disease. The \ufb01rst compound shown to inhibit HIVreplication both in vitro (cell culture) and in vivo (HIV-infected individuals) was suramin[3,4]. However, the \ufb01rst anti-HIV agent to be licensed for clinical use (in 1987) was zidovudine. It was \ufb01rst described in 1985as an antiviral agent inhibitingthe infectivity andcytopathic effect of HTLV-III/LAV in vitro.
Discoveryfor DevelopingCountries\u2019, International Centre for Science andHighTech- nology(ICS), United Nations Industrial Development Organization(UNIDO), 3\u20135July 2008, Trieste, Italy, and at TheFourteenthInternational Congress of Virology, 10\u201315 August 2008, Istanbul, Turkey.
In these early days of anti-HIV drug research, it could hardly be foreseen that within25years of the virus being discovered we wouldnow, in2008, have at hand25anti-HIVcompounds licensed (thus formally approved) for the treatment of AIDS(Table1). These compounds fall within different categories depending on the tar- get within theHIV replicative cycle they interact with(Fig. 1). The targets that have been envisaged most intensively are:reverse tran- scription, catalysed by reverse transcriptase(RT) (RNA-dependent DNA polymerase), a speci\ufb01c viral enzyme that retrotranscribes the viral single-stranded RNA genome to double-stranded provi- ral DNA; and proteolytic processing by the viral protease, which cleaves the precursor viral polyprotein into smaller mature (both structural and functional) viral proteins. Other targets that have been recognised more recently as sites for therapeutic interven- tion are viral entry, particularlyvirus\u2013cell fusion and interaction of the viruswith its(co-)receptors, and integration of the proviral DNA into the host cell genome, a process carried out by a speci\ufb01c viral enzyme, integrase, whichdetermineswhether theHIV-infected cell and all daughter cells stemmingthereof will permanently carry the provirus.
RT inhibitors (NtRTIs); andnon-nucleosideRT inhibitors (NNRTIs). The NRTIs and NtRTIs interact with the catalytic site (that is the substrate-binding site) of the enzyme, whereas the NNRTIs inter- act with an allosteric site located at a short distance(ca. 15\u00c5) from the catalytic site(Fig. 2).
For theNRTIs and NtRTIs to interact with the substrate-binding site they need to be phosphorylated to, respectively, the triphos- phate and diphosphate forms. There are at present (in2008) seven NRTIs that have been formally approved for the treatment of HIV infections: zidovudine (AZT); didanosine (ddI); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (ABC); and
principal targets for therapeutic intervention: (co-)receptor interaction; virus\u2013cell fusion; reverse transcription(by reverse transcriptase); integration; andproteolytic processing(byviral protease). AccordingtoDeClercq.
ing site for the nucleoside reverse transcriptase inhibitors (NRTIs) and nucleotide reverse transcriptase inhibitors (NtRTIs) andthe binding site for the non-nucleoside reverse transcriptase inhibitors (NNRTIs). According to De Clercq; structure of the enzyme accordingtoTantillo et al..
emtricitabine ((-)FTC) (Fig. 3). All the NRTIs can be considered as 2\u2019,3\u2019-dideoxynucleoside (ddN) analogues and act in a similar fashion. After theyhave been taken upby the cells, they are phos- phorylated to their 5\u2019-monophosphate, 5\u2019-diphosphate and5\u2019-tri- phosphate form following the same mechanism (ddN\u2192 ddN- MP\u2192 ddNDP\u2192 ddNTP) before the latter will then act as a compet- itive inhibitor/alternate substrate of the normal deoxynucleoside triphosphate (dNTP) substrate (either dATP, dTTP, dGTP or dCTP). Speci\ufb01cally, AZT and d4T are converted to dTTP competitors, ddC, 3TC and (-)FTC are converted to dCTP competitors, ddI to a dATP competitor and ABC to a dGTP competitor, according to the follo- wing pathways: AZT\u2192 AZTMP\u2192 AZTDP\u2192 AZTTP; ddI\u2192 ddIMP
As a competitive inhibitor of the normal substrate, the ddNTP will inhibit incorporation of this substrate into the growing DNA chain; as an alternate substrate it will be incorporated into this chain (as ddNMP), thereby acting as a chain terminator (since ddNMPis missingthe3\u2019-hydroxyl group required for further chain elongation). This mode of action is exempli\ufb01ed for AZT inFig. 4 based on the original data of Mitsuya et al. and Furman et al.
NtRTIs should be clearly distinguished from the NRTIs as they are nucleotide analogues (not nucleoside analogues), which means that they only need two (not three) phosphorylation steps to be converted to their active form. Most importantly, they contain a phosphonate group that cannot be cleaved by hydrolases (esterases), which would make it more dif\ufb01cult to cleave off these compounds, once incorporated at the 3\u2019-terminal end, compared with their regular nucleotide counterparts (i.e. AZTMP, ddAMP, ddCMP, etc.). The prototype of the NtRTIs, (R)- 9-(2-phosphonomethoxypropyl)adenine (tenofovir) (Fig. 5), was \ufb01rst described in 1993. The oral prodrug form of teno- fovir, tenofovir disoproxil fumarate (TDF) (Viread\u00ae), has become one of the most frequently prescribed drugs for the treat- ment of HIV infections (AIDS). Since 2008, it has also been approved for the treatment of chronic hepatitis B virus infec- tions. The mode of action of tenofovir is further illustrated in
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