Building a better nucleoside/nucleotide analogue backbone: pharmacokinetic and resistance considerations.
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Anti-HIV Agents↗
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Prevalence of drug resistance mutations in Spain among both naive and pretreated patients.
The ERASE Spanish Study Group was founded in 1997 with the primary objective of monitoring both the prevalence and impact of the development of resistance to antiretroviral drugs in HIV-infected sentinel populations. Two major studies, one in 1997 and another in 1998, have been conducted so far. Global data and results derived from substudies are summarized in this presentation.
Adult↗
[HIV infection: DuPont Pharma presents the results of its antiretroviral agent].
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Alkynes↗
[Nikavir (phosphazide)--an antiretroviral agent: anti-HIV activity, toxicology, pharmacokinetics and some perspectives of its clinical use].
Nikavir (phosphazide) is an antiretroviral agent of the class of inhibitors of type 1 HIV reverse transcriptase. It was designed in Russia and is currently used in the medical practice for the treatment of HIV infection as the monotherapy or as a component of the combined therapy. It is characterized by high anti-HIV activity, low cytotoxicity and less frequent induction of HIV-1 variants with lower susceptibility to nikavir, as compared to azidothymidine. Unlike azidothymidine, nikavir induces no blood count shifts in the patients and belongs to the group of low toxic compounds. The tolerance of nikavir by HIV-infected patients is good and its therapeutic action in HIV-1 infection is marked.
Administration, Oral↗
Didanosine. An update on its antiviral activity, pharmacokinetic properties and therapeutic efficacy in the management of HIV disease.
Didanosine is a dideoxynucleoside analogue, which is phosphorylated to the active metabolite dideoxyadenosine triphosphate (ddATP) intracellularly. At therapeutic concentrations, ddATP inhibits HIV replication by inhibiting HIV reverse transcriptase. Didanosine is established as a first-line treatment for patients with HIV disease and has recently been shown to be superior to zidovudine monotherapy in the treatment of patients with intermediate-stage HIV infection. In clinical practice, however, combination regimens of antiretroviral drugs are generally considered preferable to monotherapy as first-line treatment for most patients with HIV disease. Importantly, 2 large multicentre studies have demonstrated that combination therapy with didanosine and zidovudine was more effective than zidovudine monotherapy in delaying disease progression and death in patients with intermediate or advanced HIV disease. In other comparative studies, improvements in surrogate markers of HIV disease were generally greater in patients who received combination therapy than in recipients of antiretroviral drug monotherapy. Improvements in surrogate markers were also observed in children who received didanosine monotherapy in several clinical trials. Although the efficacy of combination antiretroviral drug therapy has not yet been investigated extensively in children, a combination regimen of didanosine and zidovudine was well tolerated and achieved beneficial effects on surrogate markers if HIV disease. In addition, preliminary findings of a larger study have shown that disease progression was delayed in children and adolescents who received didanosine plus zidovudine combination therapy compared with those receiving zidovudine monotherapy. Didanosine has a tolerability profile that is distinctly different from that of zidovudine. In particular, didanosine exhibits only minimal haematological toxicity when administered either as a single agent or in combination with zidovudine. The most serious dose-limiting adverse effects associated with didanosine treatment are peripheral neuropathy and pancreatitis. In conclusion, didanosine monotherapy is an effective treatment of HIV infection. However, combination antiretroviral therapy is the optimal treatment strategy for most patients, and didanosine is now firmly established as a component of combination antiretroviral drug regimens for the first-line treatment of patients with HIV disease.
Anti-Bacterial Agents↗
Mechanistic studies of early pausing events during initiation of HIV-1 reverse transcription.
We have investigated the role of sequences that surround the primer binding site (PBS) in the reverse transcriptase-mediated initiation of (-) strand DNA synthesis in human immunodeficiency virus type 1. In comparisons of reverse transcription initiated from either the cognate primer tRNALys.3 or a DNA primer D-Lys.3, bound to PBS sequences, we observed that a +3 pausing site occurred in both circumstances. However, the initiation reaction with tRNALys.3 was also characterized by a pausing event after incorporation of the first nucleotide. Alteration of sequences at the 5'-end instead of the 3'-end of the PBS resulted in elimination of the +3 pausing site, suggesting that this site was template sequence-dependent. In contrast, the pausing event at the +1 nucleotide position was still present in experiments that employed either of these mutated RNA templates. The mutations at the 5'-end of the PBS also caused a severely diminished rate of initiation and the strong arrest of reactions at the +1 stage when tRNALys.3 was used as primer. Therefore, we propose that the +1 pausing event is an initiation-specific event in regard to reactions primed by tRNALys.3 and that sequences at the 5'-end of the PBS may facilitate the release of reverse transcription from initiation to elongation.
Base Sequence↗
Breast cancer resistance protein (BCRP/ABCG2) induces cellular resistance to HIV-1 nucleoside reverse transcriptase inhibitors.
Breast cancer resistance protein (BCRP/ABCG2) is a novel member of ATP- binding cassette transporters, which induce multidrug resistance in cancer cells. We found that a high level of BCRP expression in CD4+ T cells conferred cellular resistance to human immunodeficiency virus type-1 (HIV-1) nucleoside reverse transcriptase inhibitors. The cell line MT-4/DOX 500 was established through the long-term culture of MT-4 cells in the presence of doxorubicin (DOX) and had reduced sensitivity to not only DOX but also zidovudine (AZT). MT-4/DOX 500 cells showed reduced intracellular accumulation and retention of DOX and increased ATP-dependent rhodamine 123 efflux. The cells were also resistant to several anticancer agents such as mitoxantrone, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin, and 7-ethyl-10-hydroxycamptothecin. AZT was 7.5-fold less inhibitory to HIV-1 replication in MT-4/DOX 500 cells than in MT-4 cells. Furthermore, the anti-HIV-1 activity of lamivudine was severely impaired in MT-4/DOX 500 cells. In contrast, the antiviral activity of non-nucleoside reverse transcriptase inhibitors and protease inhibitors was not affected in the cells. MT-4/DOX 500 cells expressed glycosylated BCRP but not P-glycoprotein (ABCB1), multidrug resistance protein 1, 2, or 4 (ABCC1, -2, or -4), or lung resistance-related protein. In addition, the BCRP-specific inhibitor fumitremorgin C completely abolished the resistance of MT-4/DOX 500 cells to AZT as well as to DOX. An analysis for intracellular metabolism of AZT suggests that the resistance is attributed to the increase of ATP-dependent efflux of its metabolites, presumably AZT 5'-monophosphate, in MT-4/DOX 500 cells.
ATP Binding Cassette Transporter, Subfamily G, Mem↗
[Progress in HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs)].
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Alkynes↗
Impact of highly active antiretroviral therapy on CD4+ T cells and viral load of children with AIDS: a population-based study.
In this study, we sought to characterize the changes over time at the population level on CD4(+) T cells and plasma viral load (VL) levels of HIV-1-infected children with or without AIDS. We carried out a retrospective study in 114 HIV-infected children during the calendar period that a highly active antiretroviral therapy (HAART) protocol was used. The HAART protocol consisted of three drugs: nucleoside analogue HIV-1 reverse transcriptase inhibitors, and/or HIV protease inhibitors, and/or nonnucleoside analogue HIV-1 reverse transcriptase inhibitors. The mean of CD4(+) T cells percentage and log(10) VL per calendar year were stratified by AIDS diagnostic. As new HAART strategies become available, an increase of CD4(+) T cells and a decrease of VL were observed over time, in children with and without AIDS. In 2001, children with AIDS reached values of CD4(+) T cells and VL similar to children without AIDS. In conclusion, our study shows that the generalized use of HAART has permitted improvement in immunological and virological status of HIV-infected children without AIDS, and more importantly in children with AIDS.
Antiretroviral Therapy, Highly Active↗
Synthesis, anti-HIV, and cytotoxic activity of new AZT conjugates of steroid acids.
In an attempt to discover potent anti-HIV agents devoid of the serious toxicity of the current HIV-reverse transcriptase inhibitors, three steroid prodrugs of AZT have been synthesized and their anti-HIV profiles determined with CEM-SS cell line. Two of the prodrugs were active against HIV, though weaker than AZT. The third agent was totally inactive against HIV. However, it demonstrated remarkably high anti-growth activities. Further experiments established that growth inhibition of the third agent was caused by induction of apoptosis rather than general necrosis.
Animals↗
Evaluation of current approaches to inhibit HIV entry.
Highly active inhibitors of human immunodeficiency virus (HIV) reverse transcriptase and protease have made it possible to dramatically reduce virus load in HIV-positive individuals. However, the presence of viral reservoirs, the emergence of drug-resistant HIV variants and the side effects of these compounds call for research into new drugs that target different stages of the viral life cycle. One attractive target is the first step in HIV replication: entry of virus into cells. HIV entry is initiated by the attachment of the virus to the host cell membrane, which is some cases involves binding to attachment factors such as DC-SIGN. Subsequent interaction of the envelope protein (Env) with the CD4 receptor causes conformational changes that enable Env to interact with a coreceptor, generally the chemokine receptors CCR5 or CXCR4. Coreceptor engagement triggers the final conformational changes in Env, which mediate lipid mixing between the viral and cellular membranes. All of these steps are potential targets for therapeutic intervention: targeting proteins that mediate viral attachment may reduce HIV transmission, while receptor blockade will inhibit virus entry. Highly conserved domains in Env which bind to CD4 and coreceptor are promising targets for broadly neutralizing antibodies, and peptide inhibitors that bind to Env and that block membrane fusion are in advanced clinical trials. These new approaches may supplement current HIV therapy and may assist in the development of an HIV vaccine.
Anti-HIV Agents↗
Efavirenz: new preparation. An alternative to HIV protease inhibitors.
(1) Efavirenz, a non nucleoside HIV reverse transcriptase inhibitor, is indicated, in combination with other antiretroviral drugs, for the treatment of HIV infection. (2) The methodologically sound clinical file is limited to trials based on validated surrogate end points (viral load) and involving patients in the early stages of HIV infection. (3) Two dose-finding studies favour a dose regimen of 600 mg in a single daily intake for adults. (4) Interim results of three ongoing trials are also available. After 48 weeks of treatment, three-drug regimens comprising efavirenz plus two nucleoside inhibitors were more effective on viral load than three-drug regimens comprising indinavir plus two nucleoside inhibitors. In another trial, after 24 weeks of treatment, a three-drug regimen combining efavirenz and two nucleoside inhibitors was no more effective on viral load than a three-drug regimen comprising nelfinavir and two nucleoside inhibitors. (5) It remains to be determined if four-drug regimens comprising efavirenz, a protease inhibitor and two nucleoside inhibitors are superior to three-drug regimens. (6) Data on the safety profile of efavirenz show mainly neuropsychological and cutaneous disorders. The severity of cutaneous effects in children needs further assessment.
Anti-HIV Agents↗
Concurrent analysis of nucleoside reverse transcriptase inhibitors in a pool of endogenous nucleosides by short-end injection-capillary electrochromatography on a beta-cyclodextrin-bonded stationary phase.
As part of our on-going study of the analysis of anti-human immunodeficiency virus (HIV) nucleosides, a capillary electrochromatography (CEC) method has been developed for the concurrent analysis of nucleoside HIV reverse transcriptase inhibitors (NRTIs) in a pool of endogenous nucleosides. Up to now, beta-cyclodextrin-bonded silica stationary phases have mainly been dedicated to the separation of enantiomers; however, these polysaccharides can be also be used in achiral way. This work aims at showing how CEC performed on a beta-cyclodextrin-bonded silica stationary phase can be used to concurrently resolve zidovudine (AZT), lamivudine (3TC), didanosine (ddA) and its administrated form (ddI), stavudine (d4T) and hivid (ddC) in a mixture of adenosine (A), cytidine (C), guanosine (G), thymidine (T) and uridine (U). The influence of several parameters (pH buffer, ionic strength, acetonitrile content, temperature and voltage) on both the retention times and the retention factors has been investigated using the short-end injection technique to achieve baseline separation in a short-time analysis before quantitation. Moreover, the retention factors of the charged solutes in short-end injection-CEC were calculated using theoretically derived equations, allowing for the actual voltage drop in the packed section of the semipacked CEC capillary.
Acetonitriles↗
Molecular aspect of HIV-1 resistance to zidovudine and its reversal.
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Drug Resistance, Microbial↗
Synthesis and anti-HIV-1 activity of novel 2,3-dihydro-7H-thiazolo[3,2-a]pyrimidin-7-ones.
Appropriately substituted 2,3-dihydro-7H-thiazolo[3,2-a]pyrimidin-7-ones 9-12 and 18 were considered as annulated analogues of HEPT (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-thymine), and some of these compounds were also found active against HIV-1, the most active one being 2,3-dihydro-5-[(3,5-dimethylphenyl)methyl]-3-ethoxy-6-ethyl-7H- thiazolo[3,2-a]pyrimidin-7-one (10b). S-Alkylation of 5-alkyl-6-(arylmethyl)-2-thiouracils 1-4 was performed with 2-bromoacetaldehyde acetals to furnish the S-[bis(alkoxy)ethyl] derivatives 5-8 and with allyl bromide to furnish S-allyl derivatives 17. The target compounds 9-12 were obtained by an N1 regioselective intramolecular cyclization reaction of silylated 5-8 using trimethylsilyl trifluoromethanesulfonate (TMS triflate) as the catalyst. Treatment of the S-allyl derivatives 17 with bromine in dry methylene chloride afforded the 3-(bromomethyl) derivatives 18.
Alkylation↗
The pseudocalanolides: structure revision of calanolides C and D.
Nmr spectra of synthetic structures corresponding to those initially reported for natural compounds calanolide C [1] and calanolide D [2] showed some subtle differences from those of the natural products. Further analysis has resulted in revision of the structures of the natural compounds, now renamed pseudocalanolides C [3] and D [4]. The absolute stereochemistry of pseudocalanolide C was established as [6S, 7S, 8R] using the modified Mosher's method.
Coumarins↗
5-hydroxyramulosin, a new natural product produced by Phoma tropica, a marine-derived fungus isolated from the alga Fucus spiralis.
The fungus Phoma tropica was isolated from the inner tissue of the marine brown alga Fucus spiralis. After large-scale cultivation the fungus was investigated for its secondary metabolite content and found to contain the new natural product 5-hydroxyramulosin ( 1) together with 7-methoxycoumarin. Both structures were elucidated using spectroscopic methods, mainly 1D and 2D NMR, and in the case of 1, a single crystal X-ray diffraction analysis.
Ascomycota↗
Chemical synthesis and biological characterization of phosphorothioate analogs of 2', 5'-3'-deoxyadenylate trimer.
In continued studies to elucidate the requirements for binding to and activation of the 2',5'-oligoadenylate (2-5A) dependent endoribonuclease (RNase L), four 2-5A trimer analogs were examined to evaluate the effect of chirality of phosphorothioate substitution on biological activity. The chemical syntheses and purification of the four isomers of P-thio-3'-deoxyadenylyl-(2'-5')-P-thio-3'- deoxyadenylyl-(2'-5')-3'-deoxyadenosine, by the phosphoramidite approach, is described. The isolated intermediates were characterized by elemental and spectral analyses. The fully deblocked compounds were characterized by 1H and 31P NMR and HPLC analyses. The 2',5'-(3'dA)3 cores with either Rp or Sp chirality in the 2',5'-internucleotide linkages will bind to but will not activate RNase L. This is in contrast to 2',5'-A3 core analogs with either RpRp or SpRp phosphorothioate substitution in the 2',5'-internucleotide linkages which can bind to and activate RNase L. There are also marked differences in the ability of the 2',5'-A3 analogs to activate RNase L following introduction of the 5'-monophosphate. For example, the 5'monophosphates of 2',5'-(3'dA)3-RpRp and 2',5'-(3'dA)3-SpRp can bind to and activate RNase L, whereas the 5'-monophosphates of 2',5'-(3'dA)3-RpSp and 2',5'-(3'dA)3-SpSp can bind to but can not activate RNase L.
Binding, Competitive↗