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PubMed2002

Discovery of second generation quinazolinone non-nucleoside reverse transcriptase inhibitors of HIV-1.

An intensive research effort to identify potent, viable drugs for the management of acquired immunodeficiency syndrome (AIDS) resulted in the development of SUSTIVA (efavirenz), the first non-nucleoside reverse transcriptase inhibitor (NNRTI) approved by the FDA as a preferred first-line therapy. The search for NNRTIs that possess a broader activity spectrum against mutant viral forms of human immunodeficiency syndrome type-I reverse transcriptase culminated in the discovery that trifluoromethyl-containing quinazolin-2(1H)-ones possess potent activity as non-nucleoside reverse transcriptase inhibitors (NNRTIs). This chapter reviews the discovery and structure activity relationships that resulted in the identification and subsequent preclinical and clinical development of four quinazolinone NNRTIs at the DuPont Pharmaceuticals Company.

Anti-HIV Agents↗
PubMed1994

Novel series of TSAO-T derivatives. Synthesis and anti-HIV-1 activity of 4-, 5-, and 6-substituted pyrimidine analogues.

Several 4-, 5-, and 6-substituted pyrimidine analogues of the new anti-HIV-1 lead compound [1-[2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]thymine] -3'-spiro-5''-(4''-amino-1'',2''-oxathiole 2'',2''-dioxide) (TSAO-T) have been prepared and evaluated as inhibitors of HIV-1 and HIV-2 replication in cell cultures. Reaction of 1,2-di-O-acetyl-5-O-benzoyl-3-C-cyano-3-O-mesyl-D-ribofuranose with 5-substituted pyrimidine bases, followed by treatment with Cs2CO3, afforded, stereoselectively, beta-D-ribofuranosyl-3'-spironucleosides. 2',5'-O-Deacylation and subsequent treatment with tert-butyldimethylsilyl chloride gave the TSAO-5-substituted pyrimidine derivatives. Reaction of 5-halogen-TSAO derivatives with nucleophiles gave 6-substituted-TSAO analogues. Treatment of TSAO-pyrimidine analogues with POCl3/1,2,4-triazole and methylamine or di-methylamine afforded the 4-substituted pyrimidine compounds. Several substituted TSAO-thymine, TSAO-uracil, and TSAO-cytosine derivatives were found to be superior to their unsubstituted TSAO congeners with regard to their antiviral and/or cytotoxic properties.

Antiviral Agents↗
PubMed1993

Metabolism of carbovir, a potent inhibitor of human immunodeficiency virus type 1, and its effects on cellular metabolism.

Carbovir (CBV) [the (--)-enantiomer of the carbocyclic analog of 2',3'-dideoxy-2',3'-didehydroguanosine] is a potent inhibitor of human immunodeficiency virus type 1 (HIV) replication in vitro. We have characterized the metabolism of CBV and its effect on cellular metabolism in an effort to better understand its mechanism of action. CBV was primarily metabolized to the 5'-triphosphate of CBV (CBV-TP) to concentrations sufficient to inhibit HIV reverse transcriptase. Infection of CEM cells with HIV did not affect the metabolism of CBV. In CEM cells, there was no evidence of the degradation of CBV by purine nucleoside phosphorylase. The half-life of CBV-TP in CEM cells was 2.5 h, similar to that of the 5'-triphosphate of zidovudine (AZT). However, unlike the levels of the 5'-triphosphate of AZT, CBV-TP levels declined without evidence of a plateau. CBV did not affect the metabolism of AZT, and AZT did not affect the metabolism of CBV. A small amount of CBV was incorporated into DNA in intact CEM cells, and this incorporation was increased by incubation with mycophenolic acid, an inhibitor of IMP dehydrogenase. CBV specifically inhibited the incorporation of nucleic acid precursors into DNA but had no effect on the incorporation of radiolabeled precursors into RNA or protein. CBV did not decrease the level of TTP, dGTP, dCTP, or dATP. These results suggested that the cytotoxicity of CBV was due to the inhibition of DNA synthesis. Further studies are necessary to identify the target(s) responsible for growth inhibition.

Antiviral Agents↗
PubMed2001

Circulating metabolites of the human immunodeficiency virus protease inhibitor nelfinavir in humans: structural identification, levels in plasma, and antiviral activities.

Nelfinavir mesylate (Viracept, formally AG1343) is a potent and orally bioavailable human immunodeficiency virus (HIV) type 1 (HIV-1) protease inhibitor (K(i) = 2 nM) and is being widely prescribed in combination with HIV reverse transcriptase inhibitors for the treatment of HIV infection. The current studies evaluated the presence of metabolites circulating in plasma following the oral administration of nelfinavir to healthy volunteers and HIV-infected patients, as well as the levels in plasma and antiviral activities of these metabolites. The results showed that the parent drug was the major circulating chemical species, followed in decreasing abundance by its hydroxy-t-butylamide metabolite (M8) and 3'-methoxy-4'-hydroxynelfinavir (M1). Antiviral assays with HIV-1 strain RF-infected CEM-SS cells showed that the 50% effective concentrations (EC50) of nelfinavir, M8, and M1 were 30, 34, and 151 nM, respectively, and that the corresponding EC50 against another HIV-1 strain, IIIB, in MT-2 cells were 60, 86, and 653 nM. Therefore, apparently similar in vitro antiviral activities were demonstrated for nelfinavir and M8, whereas an approximately 5- to 11-fold-lower level of antiviral activity was observed for M1. The active metabolite, M8, showed a degree of binding to human plasma proteins similar to that of nelfinavir (ca. 98%). Concentrations in plasma of nelfinavir and its metabolites in 10 HIV-positive patients receiving nelfinavir therapy (750 mg three times per day) were determined by a liquid chromatography tandem mass spectrometry assay. At steady state (day 28), the mean plasma nelfinavir concentrations ranged from 1.73 to 4.96 microM and the M8 concentrations ranged from 0.55 to 1.96 microM, whereas the M1 concentrations were low and ranged from 0.09 to 0.19 microM. In conclusion, the findings from the current studies suggest that, in humans, nelfinavir forms an active metabolite circulating at appreciable levels in plasma. The active metabolite M8 may account for some of the antiviral activity associated with nelfinavir in the treatment of HIV disease.

Blood Proteins↗
PubMed2004

Diversity-oriented solid-phase synthesis and biological evaluation of oligonucleotide hairpins as HIV-1 RT RNase H inhibitors.

The inhibitory potencies of several hairpins comprising DNA, RNA and 2',5'-linked RNA segments were assessed against the RNase H activity of the human immunodeficiency virus reverse transcriptase (HIV-1 RT), an indispensable enzyme for HIV genomic replication. The hairpin library was constructed via diversity-oriented nucleic-acid synthesis (DONAS), an approach inspired from traditional split-pool synthesis. DONAS provided access to an array of oligonucleotide hairpins possessing distinct conformational, structural and biological properties. The inhibitory potency of these compounds was highly specific towards HIV-1 RT RNase H and strongly depended on the structure of both the stem and tetraloop. Hairpins that have an overall A-type geometry are better inhibitors of RNase H activity than hairpins with 'intermediate' or B-type conformations, although interestingly, the inhibitory activity is quite sensitive to the nucleotide sequence in both the stem and loop regions of the hairpin. The most potent hairpins bear a 3',5'-linked rather than 2',5'-linked RNA loop, but the latter is necessary for activity of hairpins consisting of DNA stems. Inhibitory activity was essentially independent of hairpin thermal stability. The potent hairpins also demonstrated high nuclease resistance in biological media, particularly those bearing a 2',5'-linked tetraloop. These studies collectively bring into light a new class of nucleic acid aptamers that act exclusively upon the retroviral RNase H domain in vitro, and thus represent novel lead compounds for the development of specific and potent HIV-1 RT inhibitors.

Anti-HIV Agents↗
PubMed2000

Analysis of HIV type 1 reverse transcriptase: comparing sequences of viral isolates with mutational data.

A result of the high level of mutagenesis during HIV-1 viral replication is that many, if not most, HIV-1 virions and proviruses are defective and are not infectious. There is a vast amount of HIV-1 sequence data available. Unless any particular sequence is shown to be from a stable DNA clone (e.g., lambda) that can transfect cells and produce virions, then it is not known if that sequence was from an infectious HIV-1. Most sequences have not been shown to be from infectious clones. We have reported a saturation mutagenesis of a 109-amino acid region of the HIV-1 reverse transcriptase, in which we assayed the effects of 366 single-amino acid substitutions. We examined a set of sequences in the Los Alamos HIV-1 sequence database. We found that none of the sequences derived from stable infectious clones had substitutions that produce an inactive reverse transcriptase. However, we found that other sequences in this database had substitutions that inactivate the reverse transcriptase. We predict that these sequences are not from infectious clones. This method may also be useful for evaluating the sequences of other viruses.

Amino Acid Sequence↗
PubMed1999

Kinetic analysis of the effect of HIV nucleocapsid protein (NCp) on internal strand transfer reactions.

The mechanism of HIV reverse transcriptase (RT) catalyzed strand transfer synthesis (i.e., switching of the primer to a new template) from internal regions on RNA templates in the presence and absence of HIV nucleocapsid protein (NCp) was investigated. Two different systems each consisting of DNA-primed RNA donor (on which primer extension initiated) and acceptor (to which DNAs initiated on the donor could transfer) templates were used to determine kinetic parameters of strand transfer. The donor and acceptor shared an internal region of homology where homologous strand transfer could occur. The rate of strand transfer at various acceptor concentrations was determined by monitoring the production of transfer products over time. These rates were used to construct Lineweaver-Burk plots. In each system, NCp increased the Vmax about 3-fold while the Km for acceptor template was decreased severalfold. NCp's effects on RT extension ranged from no effect to inhibition depending on the primer-template used. The lowered Km shows that NCp increases the affinity of the acceptor template for the transferring DNA. Vmax increases despite the inhibition of RT extension. The increased Vmax implies a stimulatory mechanism that cannot be mimicked by high acceptor concentrations. Therefore, NCp does not act by merely increasing the effective concentration of nucleic acids.

Catalysis↗
PubMed1989

Serum capacity to inhibit reverse transcriptase in vitro distinguishes HIV-1 infection from HIV-2 or SIV infection.

The inhibition of HIV-1 and SIV reverse transcriptase by human and rhesus macaque serum positive for HIV-1 or HIV-2/SIV antibodies was studied. The domain to which reverse transcriptase-inhibiting antibodies were elicited appeared to be highly antigenic. A total of 67% (48 of 72) of individuals had HIV-1 reverse transcriptase-inhibiting (RTI) antibodies 1 year after seroconversion for HIV-1, 90% (9 of 10) of HIV-2 antibody positive persons had SIV RTI antibodies, and all four experimentally SIV-infected rhesus macaques developed SIV RTI antibodies. Low cross-reactivity between HIV-1 and HIV-2/SIV RTI antibodies was observed. Of 10 HIV-1 RTI sera, 2 reduced SIV RT activity by more than 50% (mean reduction 85 versus 24%). Only 1 of 9 SIV RTI human sera reduced HIV-1 RT (mean reduction 74 versus 25%). This serum, however, showed a shared reactivity against both HIV-1 and HIV-2. These results indicate that the HIV-1 domain inducing RTI antibodies is antigenically different from the HIV-2/SIV domain.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Proteolytic processing of an HIV-1 pol polyprotein precursor: insights into the mechanism of reverse transcriptase p66/p51 heterodimer formation.

HIV-1 reverse transcriptase (RT) is a heterodimer comprising a 66 kDa subunit (p66) and a p66-derived 51 kDa subunit (p51). RT is translated as part of a larger gag-pol polyprotein and subsequently processed to the p66/p51 heterodimer by HIV-1 protease (PR) during viral maturation. The processing events involved in the formation of the RT p66 and p51 subunits and the pathway(s) of RT dimer formation are poorly characterized. Attempts to study the kinetics of PR-catalyzed formation of p66/p51 HIV-1 RT in isolated HIV virions produced in the presence of HIV PR inhibitors were unsuccessful due to difficulties in removal of the tight-binding inhibitor to initiate proteolytic processing. Accordingly, an inducible bacterial expression vector encoding a 90 kDa pol polyprotein fragment was constructed. Following expression in Escherichia coli, the pol polyprotein underwent time-dependent proteolytic processing to the RT p66/p51 heterodimer. This processing was catalyzed entirely by HIV-1 PR since mutations that inactivate PR prevented RT heterodimer formation. The kinetics of RT processing follow an ordered sequential pathway in which RT p66 is first excised from the pol polyprotein, followed by formation of the p51 subunit. Processing of the p66 subunit to form p51 apparently proceeds through a p66/p66 RT homodimer intermediate since the L234A mutation in RT, a mutation that prevents RT dimerization, resulted in the formation of RT p66 only. These results provide the first experimental data defining the pathway for the HIV-1 PR catalyzed formation of the p66/p51 HIV-1 RT heterodimer.

Animals↗
PubMed1999

HIV resistance to zidovudine: the role of pyrophosphorolysis.

Zidovudine-resistant strains of HIV became apparent in many patients soon after advent of zidovudine (AZT) monotherapy. While this resistance could be unequivocally correlated with multiple mutations in HIV reverse transcriptase (D67N, K70R, T215F/Y, K219Q), the mechanism or phenotype for this resistance has remained obscure for more than a decade, despite active investigation. Recent studies indicate that AZT resistance may be related to removal of chain-terminating AZT from the 3'-terminus of the primer, by a process known as pyrophosphorolysis. This process is catalyzed by HIV-1 reverse transcriptase (RT), and is the reverse reaction of DNA polymerization. The D67N/K70R mutations result in a significantly increased rate of RT-catalyzed pyrophosphorolysis at physiological levels of pyrophosphate, which leads to a decrease in the extent of AZT chain termination of nascent viral DNA. The potential replication deficit of an increased reverse reaction during DNA synthesis is compensated by increased DNA synthesis processivity, a phenotype that results from the T215F/Y/K219Q mutations in RT. The net result of these multiple phenotypes imparted by the multiple mutations in RT is the facile synthesis of full-length viral DNA in the presence of AZT. Copyright 1999 Harcourt Publishers Ltd.

Journal Article↗
PubMed1994

5-Chloro-2',3'-dideoxy-3'-fluorouridine (935U83), a selective anti-human immunodeficiency virus agent with an improved metabolic and toxicological profile.

5-Chloro-2',3'-dideoxy-3'-fluorouridine (935U83) is a selective anti-human immunodeficiency virus (HIV) agent. When tested in phytohemagglutinin-stimulated normal human peripheral blood lymphocytes against fresh clinical isolates of HIV type 1 (HIV-1) obtained from patients naive to AZT (3'-azido-3'-deoxythymidine [zidovudine]), 935U83 inhibited virus growth with an average 50% inhibitory concentration (IC50) of 1.8 microM; corresponding IC50s were 0.10 microM for FLT (3'-deoxy-3'-fluorothymidine) and 0.23, 0.49, and 0.03 microM for the approved agents AZT, ddI (2',3'-dideoxyinosine), and ddC (2',3'-dideoxycytosine), respectively. Importantly, 935U83 retained activity against HIV strains that were resistant to AZT, ddI, or ddC. Of additional interest, we were unable to generate virus which was resistant to 935U83 by passaging either HXB2 (AZT-sensitive) or RTMC (AZT-resistant) strains in the presence of high concentrations of 935U83. The anabolic profile of 935U83 was similar to that of AZT, and 935U83 triphosphate was a potent inhibitor of HIV-1 reverse transcriptase. Pharmacokinetic evaluation showed good oral bioavailability (86% in mice and 60% in monkeys) and less extensive metabolism to the glucuronide relative to AZT. 935U83 showed low toxicity. In an in vitro assay for toxicity to a human erythrocyte progenitor, erythroid burst-forming unit (BFU-E), the IC50 for 935U83 (> 400 microM) was more than 1,000-fold those of FLT (0.07 microM) and AZT (0.30 microM). Mild reversible reductions in erythrocytes and associated parameters were seen in mice dosed orally with 2,000 mg of 935U83 per kg per day for 1 and 6 months. In monkeys dosed orally with up to 700 mg/kg/day for 1 and 6 months, the only possible treatment-related finding was cataracts in 1 of 12 animals given the intermediate dose of 225 mg/kg/day. At the highest doses in mice and monkeys, maximal concentrations in plasma were more than 100-fold the anti-HIV IC50s against clinical isolates. This safety profile in animals compares very favorably with that of any of the anti-HIV drugs approved to date and has led us to begin evaluation of 935U83 in patients with HIV infection.

Animals↗
PubMed2006

Hypersusceptibility to substrate analogs conferred by mutations in human immunodeficiency virus type 1 reverse transcriptase.

Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) contains four structural motifs (A, B, C, and D) that are conserved in polymerases from diverse organisms. Motif B interacts with the incoming nucleotide, the template strand, and key active-site residues from other motifs, suggesting that motif B is an important determinant of substrate specificity. To examine the functional role of this region, we performed "random scanning mutagenesis" of 11 motif B residues and screened replication-competent mutants for altered substrate analog sensitivity in culture. Single amino acid replacements throughout the targeted region conferred resistance to lamivudine and/or hypersusceptibility to zidovudine (AZT). Substitutions at residue Q151 increased the sensitivity of HIV-1 to multiple nucleoside analogs, and a subset of these Q151 variants was also hypersusceptible to the pyrophosphate analog phosphonoformic acid (PFA). Other AZT-hypersusceptible mutants were resistant to PFA and are therefore phenotypically similar to PFA-resistant variants selected in vitro and in infected patients. Collectively, these data show that specific amino acid replacements in motif B confer broad-spectrum hypersusceptibility to substrate analog inhibitors. Our results suggest that motif B influences RT-deoxynucleoside triphosphate interactions at multiple steps in the catalytic cycle of polymerization.

Amino Acid Motifs↗
PubMed2000

Abacavir: new preparation. Risks limit the value.

(1) Abacavir, a nucleoside inhibitor of HIV reverse transcriptase, is indicated for the treatment of HIV-infected adults, in combination with other antiretroviral drugs. (2) The assessment file is limited mainly to trials involving patients who have never received other antiretroviral drugs. There are no comparisons of abacavir plus two other nucleoside inhibitors versus three nucleoside inhibitors or versus one non nucleoside inhibitor plus two nucleoside inhibitors. (3) According to initial results the optimal dose regimen of abacavir in adults appears to be 300 mg twice a day. The lamivudine + zidovudine + abacavir combination reduces viral load more strongly than the lamivudine + zidovudine combination in patients not previously treated with antiretroviral drugs. Preliminary results suggest that the same applies to patients previously treated with antiretroviral drugs. (4) A trial involving 562 previously untreated patients showed that the effect of the abacavir + lamivudine + zidovudine combination (total of 4 tablets a day) was not significantly different from that of the indinavir + lamivudine + zidovudine combination (8 tablets a day) after 48 weeks of treatment. (5) In clinical trials, approximately 3% of adults and 5% of children had hypersensitivity reactions to abacavir. Under the strict conditions of the trials it was not always possible to avoid abacavir rechallenge, which carries a risk of a new, potentially fatal hypersensitivity reaction. (6) The risk-benefit ratio of abacavir is currently unfavourable in children, who must not be prescribed the drug. (7) The risk of drug interactions with abacavir is low.

Adult↗
PubMed1995

Sensitivity/resistance profile of a simian immunodeficiency virus containing the reverse transcriptase gene of human immunodeficiency virus type 1 (HIV-1) toward the HIV-1-specific non-nucleoside reverse transcriptase inhibitors.

To develop an animal model for the therapy of AIDS with human immunodeficiency virus type 1 (HIV-1)-specific reverse transcriptase (RT) inhibitors, we recently constructed a hybrid simian immunodeficiency virus (SIV)/HIV-1 in which the RT gene of SIV was replaced by the RT gene of HIV-1. This chimaeric virus, designated RT-SHIV, was found to be markedly sensitive to the inhibitory effects of both nucleoside (ddN) and non-nucleoside RT inhibitors (NNRTIs). In contrast, SIV was inhibited only by ddNs (i.e., 3TC and AZT), but not NNRTIs. When RT-SHIV was grown in the presence of 3TC, nevirapine, TSAO-m3T or the thiocarboxanilide UC-42 drug-resistant mutant virus strains emerged in cell culture as rapid as for HIV-1(IIIB). The antiviral sensitivity/resistance spectrum of the mutant RT-SHIV strains against NNRTIs and ddNs, and the nature of the mutations that appeared in their RT were similar to those of the mutant HIV-1 strains that were selected under identical experimental conditions. Infection of macaques with RT-SHIV may be a useful tool for studying the mechanism of NNRTI-resistance development and the therapy of NNRTI-resistant viruses in an animal model.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Metal-ion stoichiometry of the HIV-1 RT ribonuclease H domain: evidence for two mutually exclusive sites leads to new mechanistic insights on metal-mediated hydrolysis in nucleic acid biochemistry.

Crystallographic studies of the Mn(2+)-doped RNase H domain of human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) have revealed two bound Mn2+ separated by approximately 4A and surrounded by a cluster of four conserved carboxylates. Escherichia coli RNase H is structurally similar to the RNase H domain of HIV-1 RT, but requires one divalent metal cation for its activity, implying either that the HIV-1 RT RNase H domain contrasts in its ability to bind two divalent metal ions, or that the crystallographic data reflect specific use of Mn2+ and/ or the doping technique employed. Metal binding stoichiometry has been determined for Mn2+ and the biologically more relevant Mg2+ cation by solution calorimetric studies of native and recombinant p66/p51 HIV-1 RT. Three Mn2+ ions bind to HIV-1 RT apo-enzyme: one at the DNA polymerase and two at the RNase H catalytic center, the latter being consistent with crystallographic results. However, only one Mg2+ ion is bound in the RNase H catalytic center. Several mechanistic implications arise from these results, including the possibility of mutually exclusive Mg2+ binding sites that might be occupied according to the specific reaction being catalyzed by the multifunctional RNase H domain. The occurrence of distinct binding stoichiometries for Mg2+ and Mn2+ to multifunctional enzymes has previously been reported.

Calorimetry↗
PubMed1995

Phase I/II study of 3TC (lamivudine) in HIV-positive, asymptomatic or mild AIDS-related complex patients: sustained reduction in viral markers. The Lamivudine European HIV Working Group.

OBJECTIVE: To evaluate the efficacy of 3TC (lamivudine), a synthetic nucleoside analogue that inhibits HIV reverse transcriptase in vitro, as treatment for HIV-positive, asymptomatic or mild AIDS-related complex patients. DESIGN: Open-label, multinational and multicentre, non-comparative, escalating dose study. METHODS: Patients who meet the selection criteria (n = 104) were enrolled in three European countries. Ten to 15 patients were included at each of the six dose levels of 3TC (0.5, 1.0, 2.0, 4.0, 8.0, 12.0 and 20.0 mg/kg daily in two divided doses every 12 h). Virological parameters--immune-complex dissociation (ICD) assay for HIV p24 antigenaemia, plasma HIV RNA load, whole blood assay and cellular viraemia--were evaluated at weeks 0, 4, 12 and 24. RESULTS: Sustained reductions in HIV RNA load and in ICD p24 antigen levels were observed and maintained over the 12-week assessment period. Greater reductions were noted at higher doses but this trend did not reach statistical significance. In 38 patients, reductions of cell viraemia were significantly greater at 4 weeks for patients treated at higher doses of 3TC. CONCLUSION: These virological data show that 3TC is a potent inhibitor of HIV replication in HIV-positive, asymptomatic or mild ARC patients as assessed by ICD p24 antigenaemia, plasma HIV RNA load and cell viraemia.

AIDS-Related Complex↗
PubMed1992

Effect of human chorionic gonadotropin (hCG) on reverse transcriptase activity in HIV-1 infected lymphocytes and monocytes.

The majority of infants born to HIV-positive mothers are not infected in utero, suggesting that the pregnancy factors produced by fetal trophoblasts may provide protection against HIV-1 infection. Except for steroid female hormones, little is known of other pregnancy factors that may regulate either resistance or susceptibility to HIV-1. Human chorionic gonadotropin (hCG)--the major glycoprotein produced by the placental trophoblast throughout the pregnancy--was tested on reverse transcriptase activity in HIV-infected ACH-2 lymphocytes and U1 monocytes. The results suggest that low non-cytotoxic doses of hCG (0.01-1.0 IU range) may inhibit viral replication in maternal blood cells.

Cells, Cultured↗