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PubMed1994

Interaction of the reverse transcriptase of human immunodeficiency virus type 1 with DNA.

During DNA synthesis, the binding of human immunodeficiency virus (HIV) reverse transcriptase (RT) to the template-primer precedes its binding to nucleotide triphosphates. The interaction of oligonucleotide DNA with HIV-1 RT was investigated by using a gel retardation assay. Both homodimeric (p66/p66) and heterodimeric (p66/p51) isoforms of HIV-1 RT were capable of binding the DNA oligomers. Thus, all further studies on the interaction of HIV-1 RT with DNA were done with heterodimeric RT. We have studied the conditions for optimal binding. The formation of the RT-DNA complex was primer-independent, and the extent of DNA binding was indistinguishable for both single-stranded and double-stranded DNA (either blunt-ended or recessed). The DNA binding activity of the RT was found to be dependent on oligonucleotide length. HIV-1 RT binds DNA with no apparent sequence specificity. Hence, this enzyme belongs to the sequence nonspecific DNA binding proteins. The interaction was found to be independent of DNA synthesis. The formation of the RT-DNA complex was not influenced by the presence of either template-complementary or noncomplementary dNTPs, indicating that neither DNA polymerization nor binding of the RT to the dNTP affects the stability of the complex. The gel retardation assay was utilized to examine also the effect of various HIV-1 RT inhibitors (i.e., AZT-TP, ddTTP, TIBO, and 3,5,8-trihydroxy-4-quinolone) on the enzyme-DNA interaction. The results indicate differences in the modes of action of these compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiviral Agents↗
PubMed2002

Combinations against combinations: associations of anti-HIV 1 reverse transcriptase drugs challenged by constellations of drug resistance mutations.

The reverse transcriptase inhibitors still represent the majority of the clinically used anti-HIV drugs and constitute the main backbone of currently employed combinatorial regimens. A major obstacle to successfull chemotherapic eradication of HIV is the emergence of viral strains resistant to the drugs in use. Counteracting the emergence of resistance necessitates alternating the panel of agents employed. In order to rationally design alternative drug combinations, physicians not only must know the genotype of the emerging viral strains, but should also be able to correlate it with its resistant phenotype. However, resistant viral strains usually carry multiple mutations, whose reciprocal influences on the overall level of resistance are largely unknown. Moreover, the choice of agents to be combined must take in account drug-drug interactions and adverse metabolic effects. This review will outline the main pharmacological and clinical features of the currently utilised anti-reverse transcriptase drugs, as well as the correspondent resistance profiles selected during therapy. A major focus will be on the reciprocal influence of drug associations on their own metabolism as well as on the interacting effects of the selected combinations of drug resistance mutations.

Animals↗
PubMed2005

Conservation of functional domains and limited heterogeneity of HIV-1 reverse transcriptase gene following vertical transmission.

BACKGROUND: The reverse transcriptase (RT) enzyme of human immunodeficiency virus type 1 (HIV-1) plays a crucial role in the life cycle of the virus by converting the single stranded RNA genome into double stranded DNA that integrates into the host chromosome. In addition, RT is also responsible for the generation of mutations throughout the viral genome, including in its own sequences and is thus responsible for the generation of quasi-species in HIV-1-infected individuals. We therefore characterized the molecular properties of RT, including the conservation of functional motifs, degree of genetic diversity, and evolutionary dynamics from five mother-infant pairs following vertical transmission. RESULTS: The RT open reading frame was maintained with a frequency of 87.2% in five mother-infant pairs' sequences following vertical transmission. There was a low degree of viral heterogeneity and estimates of genetic diversity in mother-infant pairs' sequences. Both mothers and infants RT sequences were under positive selection pressure, as determined by the ratios of non-synonymous to synonymous substitutions. Phylogenetic analysis of 132 mother-infant RT sequences revealed distinct clusters for each mother-infant pair, suggesting that the epidemiologically linked mother-infant pairs were evolutionarily closer to each other as compared with epidemiologically unlinked mother-infant pairs. The functional domains of RT which are responsible for reverse transcription, DNA polymerization and RNase H activity were mostly conserved in the RT sequences analyzed in this study. Specifically, the active sites and domains required for primer binding, template binding, primer and template positioning and nucleotide recruitment were conserved in all mother-infant pairs' sequences. CONCLUSION: The maintenance of an intact RT open reading frame, conservation of functional domains for RT activity, preservation of several amino acid motifs in epidemiologically linked mother-infant pairs, and a low degree of genetic variability following vertical transmission is consistent with an indispensable role of RT in HIV-1 replication in infected mother-infant pairs.

Journal Article↗
PubMed1995

The orientation of binding of human immunodeficiency virus reverse transcriptase on nucleic acid hybrids.

The binding of HIV reverse transcriptase (RT) to heteroduplexes was examined using a substrate consisting of a 42 nt chimeric nucleic acid composed. (5'-->3') of 23 nt of RNA and 19 of DNA. This chimera was hybridized to an internal region of a relatively long complementary DNA or RNA. When the chimera was bound to DNA and conditions limiting cleavage to a single binding event between the enzyme and substrate were employed initial RNase H-directed cleavages occurred 19-21 nt from the chimera 5'-terminus. A 42 nt strand identical in sequence to the chimera and composed of only RNA was cleaved at the same locations. Reducing the length of the DNA portion of the chimera from 19 to 7 nt did not alter the cleavage positions, suggesting that cleavage was not coordinated by the DNA 3'-terminus. Under the same conditions cleavage was not detected when the chimera was bound to RNA. In contrast, addition of dNTPs to the DNA 3'-terminus of the chimera occurred only when the chimera was bound to RNA. The results support preferable binding of RT to RNA-DNA versus DNA-DNA hybrid regions and a model in which the orientation of binding to heteroduplexes is 5'-->3' (relative to the RNA strand), polymerase to RNase H active site, with sites associated with the DNA and RNA strand respectively.

Base Sequence↗
PubMed2006

Arylthiopyrrole (AThP) derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors: synthesis, structure-activity relationships, and docking studies (part 1).

Novel arylthio isopropyl pyridinylmethylpyrrolemethanol (AThP) derivatives 3-5, which are related to capravirine (S-1153), were synthesized and tested for their ability to block the replication cycle of HIV-1 in infected cells. The newly synthesized AThPs are active in the concentration range of 0.008-53 microM. Even if compounds 3-5 are generally less potent than S-1153, their SI values are in some cases similar to that of the reference drug. In fact, the cytotoxicities of AThPs are generally lower than that of S-1153. Compound 4e was the most active derivative of this series in cell-based assays; its potency is similar to that of S-1153 (EC(50)=8 and 3 nM, respectively), as is its selectivity index (SI=6250 and 7000, respectively). AThP derivatives were proven to target HIV-1 RT. In fact, compounds 3-5 generally inhibited the viral enzyme at concentrations similar to those observed in cell-based assays. A selected number of AThPs (4k and 5a,e) were tested against clinically relevant drug-resistant forms of recombinant reverse transcriptase (rRT) carrying the K103N and Y181I mutations. Carbamate 5e showed an approximate 240-fold decrease in activity against Y181I, but only a 10-fold loss in potency against the K103N rRT form. Docking calculations were also performed to investigate the binding mode of compounds 2, 4e, 4j, 4k and 5e into the non-nucleoside binding site of HIV-1 RT and to rationalize some structure-activity relationships and resistance data.

Binding Sites↗
PubMed1996

Mutational studies of human immunodeficiency virus type 1 reverse transcriptase: the involvement of residues 183 and 184 in the fidelity of DNA synthesis.

The high error rates characteristic of human immunodeficiency virus type-1 reverse transcriptase (HIV-1 RT) are a presumptive source of the viral hypermutability that impedes prevention and therapy of acquired immunodeficiency syndrome (AIDS). We have analyzed two mutants of HIV-1 RT by conducting a comparative study of the accuracy of DNA synthesis. Each mutant bears a single amino acid substitution adjacent to the two aspartic acid residues at positions 185 and 186 in the highly conserved DNA polymerase active site. The first mutant, Met 184-->Leu (M184L), displays a marked reduction in both misinsertion and mispair extension, suggesting a fidelity of DNA synthesis significantly higher than that of the wild-type HIV-1 RT. The second mutant, Tyr 183-->Phe (Y183F), shows a decrease in mispair extension with no significant change in misincorporation. Thus, the overall pattern of error-proneness of DNA synthesis is: wild-type HIV-1 RT > Y183F > M184L. Taken together, it is possible that residues 183 and 184 contribute to the low fidelity of DNA synthesis characteristic of the reverse transcriptases of HIV-1, HIV-2 and possibly, of other lentiviruses. Our observations may bear on the nature of potential mutations responsible for resistance to the nucleoside analogs used in chemotherapy of AIDS.

Base Sequence↗
PubMed1995

Phenethylthiazolethiourea (PETT) compounds, a new class of HIV-1 reverse transcriptase inhibitors. 1. Synthesis and basic structure-activity relationship studies of PETT analogs.

A novel series of potent specific HIV-1 inhibitory compounds is described. The lead compound in the series, N-(2-phenethyl)-N'-(2-thiazolyl)thiourea (1), inhibits HIV-1 RT using rCdG as the template with an IC50 of 0.9 microM. In MT-4 cells, compound 1 inhibits HIV-1 with an ED50 of 1.3 microM. The 50% cytotoxic dose in cell culture is > 380 microM. The chemical structure-activity relationship (SAR) was developed by notionally dividing the lead compound in four quadrants. The SAR strategy had two phases. The first phase involved optimization of antiviral activity through independent variation of quadrants 1-4. The second phase involved the preparation of hybrid structures combining the best of these substituents. Further SAR studies and pharmacokinetic considerations led to the identification of N-(2-pyridyl)-N'-(5-bromo-2-pyridyl)-thiourea (62; LY300046.HCl) as a candidate for clinical evaluation. LY300046.HCl inhibits HIV-1 RT with an IC50 of 15 nM and in cell culture has an ED50 of 20 nM.

Animals↗
PubMed1996

Interaction of human immunodeficiency virus nucleocapsid protein with a structure mimicking a replication intermediate. Effects on stability, reverse transcriptase binding, and strand transfer.

The interaction of human immunodeficiency virus (HIV) nucleocapsid protein (NCp) with a substrate closely mimicking a retrovirus replication intermediate was studied. The heteroduplex substrate consisted of a DNA and RNA of 80 and 63 nucleotides, respectively. The nucleotides at the 3' end of the DNA were complementary to those at the 3' end of the RNA such that a hybrid region of 30 base pairs could form. HIV-reverse transcriptase (RT) extended the DNA and cleaved the RNA strand of the substrate. The rates of extension and cleavage were significantly decreased when the substrate was prebound with NCp before HIV-RT addition. In assays assessing the integrity of the substrate by measuring release of the DNA strand from the heteroduplex, prebinding with NCp protected the substrate when HIV-RT was added, a result consistent with resistance to RT-mediated cleavage. In contrast, NCp significantly decreased the thermal stability of the substrate as judged by incubation of the substrate at various temperatures. In strand transfer assays, a 189-nucleotide RNA (acceptor) with an internal region complementary to all 80 nucleotides of the substrate DNA was incubated with the substrate in the presence or absence of NCp. Nucleocapsid protein stimulated strand transfer in which the substrate RNA was displaced upon binding of the DNA to the acceptor. Results are discussed with respect to the role of NCp in retroviral recombination.

Capsid↗
PubMed2000

Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity.

OBJECTIVE: This paper reviews the function of the mitochondria and the mechanisms by which nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) cause mitochondrial toxicity. BACKGROUND: Highly active antiretroviral therapy (HAART) reduces rates of morbidity and mortality due to HIV disease. However, long-term treatment with these drugs may be associated with adverse effects. Nucleoside and nucleotide analogues are potent inhibitors of HIV reverse transcriptase and have become the cornerstone of HAART. Unfortunately, these drugs have also been shown to inhibit cellular polymerases, most notably mitochondrial DNA polymerase gamma. RESULTS: Studies of the NRTIs in enzyme assays and cell cultures demonstrate the following hierarchy of mitochondrial DNA polymerase gamma inhibition: zalcitabine > didanosine > stavudine > lamivudine > zidovudine > abacavir. In vitro investigations have also documented impairment of the mitochondrial enzymes adenylate kinase and the adenosine diphosphate/adenosine triphosphate translocator. Inhibition of DNA polymerase gamma and other mitochondrial enzymes can gradually lead to mitochondrial dysfunction and cellular toxicity. The clinical manifestations of NRTI-induced mitochondrial toxicity resemble those of inherited mitochondrial diseases (ie, hepatic steatosis, lactic acidosis, myopathy, nephrotoxicity, peripheral neuropathy, and pancreatitis). Fat redistribution syndrome, or HIV-associated lipodystrophy, is another side effect attributed in part to NRTI therapy. The morphologic and metabolic complications of this syndrome are similar to those of the mitochondrial disorder known as multiple symmetric lipomatosis: suggesting that this too may be related to mitochondrial toxicity. The pathophysiology of less common adverse effects of nucleoside analogue therapy, such as diabetes, ototoxicity, and retinal lesions, may be related to mitochondrial dysfunction but have not been adequately studied. CONCLUSION: NRTls can block both HIV reverse transcriptase and mitochondrial DNA polymerase gamma. Inhibition of the latter enzyme is the most likely cause of the adverse effects associated with these drugs.

Animals↗
PubMed2004

[The anti-HIV activity of glycyrrhizic acid penta-O-nicotinate].

The anti-HIV activity of niglizin (penta-O-nicotinate of glycyrrhizic acid) and of its combinations was studied in the culture of infected MT-4 cells and in respect to the recombinant reverse HIV-1 transcriptase. Niglizin was shown to suppress effectively the HIV replication and to be a noncompetitive inhibitor of reverse transcriptase. Research of a combined anti-HIV action of niglizin and of azidothimidine (AZT) demonstrated that the preparations, when used at ratios of 1:20, 1:50, 1:200 and 1:2000, suppressed the synergetic effect both in the cell culture and in the recombinant reverse HIV transcriptase. A study of the antiviral activity of niglizin and of its joint use with AZT in respect to the AZT-resistant HIV-1 mutant showed niglizin to be more effective (ID50 = 0.134 microM) versus the "wild" strain. (ID50 = 9.64 micriM); whereas, its combined use AZT:niglizin = 1:100 displayed synergism (FIC = 0.553). The efficiency of the combined AZT/niglizin anti-HIV effect both in respect to the "wild" strain and to the AZT-resistant mutant confirms that such combinations are promising for the treatment of HIV infection.

Anti-HIV Agents↗
PubMed1999

Urea-PETT compounds as a new class of HIV-1 reverse transcriptase inhibitors. 3. Synthesis and further structure-activity relationship studies of PETT analogues.

The further development of allosteric HIV-1 RT inhibitors in the urea analogue series of PETT (phenylethylthiazolylthiourea) derivatives is described here. The series includes derivatives with an ethyl linker (1-5) and racemic (6-16) and enantiomeric (17-20) cis-cyclopropane compounds. The antiviral activity was determined both at the RT level and in cell culture on both wild-type and mutant forms of HIV-1. Most compounds have anti-HIV-1 activity on the wt in the nanomolar range. Resistant HIV-1 was selected in vitro for some of the compounds, and the time for resistant HIV-1 to develop was longer for urea-PETT compounds than it was for reference compounds. Preliminary pharmacokinetics in rats showed that compound 18 is orally bioavailable and penetrates well into the brain. The three-dimensional structure of complexes between HIV-1 RT and two enantiomeric compounds (17 and 18) have been determined. The structures show similar binding in the NNI binding pocket. The propionylphenyl moieties of both inhibitors show perfect stacking to tyrosine residues 181 and 188. The cyclopropyl moiety of the (+)-enantiomer 18 exhibits optimal packing distances for the interactions with leucine residue 100 and valine residue 179.

Administration, Oral↗
PubMed2002

ATP-dependent removal of nucleoside reverse transcriptase inhibitors by human immunodeficiency virus type 1 reverse transcriptase.

Removal of nucleoside chain terminator inhibitors mediated by human immunodeficiency virus (HIV) reverse transcriptase (RT) using ATP as an acceptor molecule has been proposed as a novel mechanism of HIV resistance. Recombinant wild-type and mutant HIV type 1 (HIV-1) RT enzymes with thymidine analog resistance mutations D67N, K70R, and T215Y were analyzed for their ability to remove eight nucleoside reverse transcriptase inhibitors in the presence of physiological concentrations of ATP. The order for the rate of removal of the eight inhibitors by the mutant RT enzyme was zidovudine (AZT) > stavudine (d4T) >> zalcitabine (ddC) > abacavir > amdoxovir (DAPD) > lamivudine (3TC) > didanosine (ddI) > tenofovir. Thymidine analogs AZT and d4T were the most significantly removed by the mutant enzyme, suggesting that removal of these inhibitors by the ATP-dependent removal mechanism contributes to the AZT and d4T resistance observed in patients with HIV expressing thymidine analog resistance mutations. ATP-dependent removal of tenofovir was 22- to 35-fold less efficient than removal of d4T and AZT, respectively. The addition of ATP and the next complementary deoxynucleoside triphosphate caused a reduction of ATP-mediated removal of d4T, ddC, and DAPD, while AZT and abacavir removal was unaffected. The reduction of d4T, ddC, and DAPD removal in the presence of the deoxynucleoside triphosphate could explain the minor changes in susceptibility to these drugs observed in conventional in vitro phenotypic assays using cells that have higher deoxynucleoside triphosphate pools. The minimal removal of abacavir, ddC, DAPD, 3TC, ddI, and tenofovir is consistent with the minor changes in susceptibility to these drugs observed for HIV mutants with thymidine analog resistance mutations.

Adenine↗
PubMed2004

A role for dNTP binding of human immunodeficiency virus type 1 reverse transcriptase in viral mutagenesis.

HIV-1 reverse transcriptase (RT) is a highly error prone DNA polymerase. We assessed whether the ability of RT to bind nucleotide substrates affects viral mutagenesis. Structural modeling predicts that the V148 and Q151 residues influence the interaction between RT and the incoming dNTP. When we introduce either a V148I or Q151N mutation, RT fidelity increases 8.7- or 13-fold, respectively, as measured by the M13 lacZalpha forward mutation assay. Interestingly, pre-steady state kinetic studies demonstrated that these mutations do not alter polymerase fidelity during the first step of mutation synthesis, misincorporation. Rather, the V148I and Q151N mutations alter RT fidelity by weakening the ability of the polymerase to complete mismatch extension, the second step of mutation synthesis. While both these mutations minimally affect the binding of RT (K(D)) to a mismatched template-primer complex (T/P), these mutant RTs are significantly impaired in their ability to bind (K(d)) and chemically incorporate (k(pol)) nucleotide substrate onto a mismatched T/P. These differences in binding and catalysis translate into 24- and 15.9-fold increase in mismatch extension fidelity for the V148I and Q151N RT mutants, respectively. Finally, we employed a cell-based pseudotyped HIV-1 mutation assay to determine whether changes in these dNTP binding residues alter RT fidelity in vivo. We found that the V148I and Q151N mutant viruses had 3.8- and 5.7-fold higher fidelities than wild-type viruses, respectively, indicating that the molecular interaction between HIV-1 RT and the dNTP substrate contributes to viral mutagenesis.

Amino Acid Substitution↗
PubMed2005

Suppression of multidrug-resistant HIV-1 reverse transcriptase primer unblocking activity by alpha-phosphate-modified thymidine analogues.

A dipeptide insertion between codons 69 and 70 together with the amino acid substitution T215Y in the reverse transcriptase (RT)-coding region of human immunodeficiency virus type 1 (HIV-1) strains are known to confer phenotypic resistance to zidovudine (AZT) and stavudine (d4T). Phenotypic resistance correlates with an increased ATP-dependent phosphorolytic activity. Nucleoside alpha-boranophosphate diastereoisomers derived from AZT and d4T were tested as substrates of a multidrug-resistant HIV-1 RT (designated as SS RT) bearing a Ser-Ser insertion at codons 69-70 and other drug resistance-related mutations, in DNA polymerization assays and ATP-mediated excision reactions. Using pre-steady-state kinetics, we show that SS RT can incorporate both R(p) and S(p) diastereoisomers, although R(p) is the preferred isomer. Chirality at the internucleotidic linkage formed upon incorporation of nucleoside alpha-boranophosphate did not affect ATP-mediated excision. As reported for AZT and d4T-terminated primers, substituting Thr, Asn or Ser for Tyr215 abrogates the ATP-dependent phosphorolytic activity on primers terminated with alpha-boranophosphate derivatives of thymidine analogues. However, unlike in the case of AZT, eliminating the dipeptide insertion in SS RT had no effect on the ATP-mediated excision of primers terminated with alpha-boranophosphate derivatives of d4T. Studies with ATP analogues showed that exchanging a non-bridging oxygen atom at the gamma-phosphate group for sulfur causes a significant reduction of the ATP-dependent phosphorolytic activity of SS RT. Interestingly, SS RT's excision activity is completely eliminated upon phosphorothioate substitution at the 3' end of primers terminated with AZT. These results suggest that phosphorothioate derivatives of currently approved drugs could be useful against excision-proficient HIV-1 strains.

Adenosine Triphosphate↗
PubMed1992

Novel non-nucleoside inhibitors of HIV-1 reverse transcriptase. 2. Tricyclic pyridobenzoxazepinones and dibenzoxazepinones.

Dibenz[b,f][1,4]oxazepin-11(10H)-ones (III), pyrido[2,3-b][1,4]benzoxazepin-6(5H)-ones (IV), and pyrido[2,3-b]- [1,5]benzoxazepin-5(6H)-ones (V) were found to inhibit human immunodeficiency virus type 1 reverse transcriptase with IC50 values as low as 19 nM. A-ring substitution has a profound effect on activity, with appropriate substituents at the positions ortho and para to the lactam nitrogen providing dramatically enhanced potency. Substitution in the C-ring is generally neutral or detrimental to activity. Although a C-ring amino substituent at the position meta to the lactam carbonyl is generally beneficial to activity, it has essentially no effect when the A-ring is optimally substituted. Like the dipyridodiazepinone nevirapine, compounds III-V are specific for HIV-1 RT, exhibiting no inhibitory activity against HIV-2 RT or other virial reverse transcriptase enzymes.

Dibenzoxazepines↗
PubMed2000

Dolichin, a new chitinase-like antifungal protein isolated from field beans (Dolichos lablab).

An antifungal protein, possessing a molecular weight of 28 kDa and an N-terminal sequence resembling chitinases, has been purified from the seeds of the field bean Dolichos lablab. The procedure involved extraction with aqueous buffer, affinity chromatography on Affi-gel blue gel, and ion exchange chromatography on CM-Sepharose. The protein, designated dolichin, exhibited antifungal activity against the fungi Fusarium oxysporum, Rhizoctonia solani, and Coprinus comatus. Dolichin was capable of inhibiting human immunodeficiency virus (HIV) reverse transcriptase and alpha- and beta-glucosidases which are glycohydrolases implicated in HIV infection. It had very low ribonuclease and cell-free translation-inhibitory activities.

Amino Acid Sequence↗
PubMed1996

Sensitive detection and quantification of particle-associated reverse transcriptase in plasma of HIV-1-infected individuals by the product-enhanced reverse transcriptase (PERT) assay.

Tests for the enzyme reverse transcriptase (RT) should permit the detection of all infectious retroviruses, provided that these are present as extracellular particles. The capability of a new procedure, named product-enhanced reverse transcriptase (PERT) assay, to detect HIV-1 in fresh human plasma was compared with that of the polymerase chain reaction (PCR) for viral RNA. Both procedures had identical dilution endpoints corresponding to 10(2) particles/ml. All 30 samples from HIV-1 positive patients at different stages contained RT activity whose level was significantly correlated with viral RNA and corresponded to 553-417,000 particles/ml. In HIV-1 low titer performance and seroconversion panels, the PERT assay detected more positives than PCR for viral RNA. Three of 160 blood donors exhibited elevated RT activity, indicating a prevalence of 1.9% (95% CI 0.4-5.3%). One positive donor, with laboratory parameters suggesting a mild chronic liver impairment, exhibited RT activity comparable to that of HIV positives, but was consistently negative by various tests for hepatitis viruses, cytomegalovirus, the HIVs and HTLVs. The results suggest that the PERT assay is more sensitive for detection of HIV-1 contamination of plasma than RNA PCR. However, it is not affected adversely by viral sequence variability, and may therefore, also detect HIV-1 subtype O, and additional retroviruses as yet undetectable by PCR.

Base Sequence↗
PubMed1995

Anti-(human immunodeficiency virus) activity of polyoxotungstates and their inhibition of human immunodeficiency virus reverse transcriptase.

Heteropolyoxotungstates of the Keggin class containing different heteroatoms were tested for inhibition of two strains of human immunodeficiency virus 1 (HIV-1); they exhibited varying antiviral activity. Compounds containing boron were inactive, only one of those containing phosphorus showed selective anti-viral activity, whereas all silicon-containing compounds exhibited significant anti-viral activity in C8166 cells infected with the IIIB strain. Their effectiveness was some 10-fold higher in JM cells with selectivity indices of about 2000. The silicotungstates were effective inhibitors of HIV reverse transcriptase, showing greater inhibition with RNA/DNA template primers than with DNA/DNA template.primer. Kinetic analysis demonstrated that they inhibit the enzyme by different mechanisms, as, of the four compounds examined, two competed with template.primer and two competed with deoxynucleoside triphosphate. Inhibition of DNA polymerase activity by these compounds was compared using polymerases from different sources, including human; although not necessarily most specific for HIV-1 reverse transcriptase, they did not inhibit all DNA polymerases to a similar degree.

Antiviral Agents↗