Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oligodeoxynucleoside methylphosphonates, nucleic acid analogues that contain nonionic, 3'-5'-linked methylphosphonate internucleotide bonds, can be used to control mRNA function in living cells. In order to use analogues of defined sequence in biochemical and biological experiments, methods have been developed to characterize the chain length and sequence of oligodeoxyribonucleoside methylphosphonates and to study their interaction with mRNA. Methylphosphonate oligomers that terminate at the 5' end with a 3'-5' internucleotide phosphodiester bond are readily phosphorylated by polynucleotide kinase. Treatment of these 32P end labeled oligomers with aqueous piperidine randomly hydrolyzes the methylphosphonate linkage and upon gel electrophoresis produces a ladder of oligomers, which allows the chain length of the oligomer to be determined. The sequence of 32P end labeled oligonucleoside methylphosphonates can be determined by a modified chemical sequencing procedure. The interaction of the oligomers with rabbit globin mRNA was studied. The oligomers hybridize with mRNA in agarose gels. The stability of the hybrids increases with increasing chain length of the oligomer. The binding site of the oligomers on mRNA can be determined by using the oligomer as a primer for reverse transcriptase. The length of the resulting transcript is determined by polyacrylamide gel electrophoresis after removal of the methylphosphonate primer by treatment with piperidine. The results indicate that binding and priming ability of the oligonucleoside methylphosphonates are affected by the secondary structure of the mRNA.
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PMID:Characterization of sequence-specific oligodeoxyribonucleoside methylphosphonates and their interaction with rabbit globin mRNA. 241 82

The activity against human immunodeficiency virus (HIV) and herpes simplex virus (HSV), of the non-polar fraction of a methanolic extract of the rootbark of Schumanniophyton magnificum was found to be present in a fraction containing the chromone secondary amine schumannificine 1. Other chromone alkaloids present in the plant were isolated and tested for inhibition of HIV and HSV infections in C8166 and Vero cells, respectively. Acyl and methyl derivatives were prepared and tested. Of all the compounds tested, schumannificine 1 displayed the greatest activity against HIV, whereas potent anti-HSV activity was observed for a number of its derivatives. The presence of a piperidine ring and unsubstituted hydroxy groups on the molecules seems to favour the anti-HIV activity. The anti-HIV activity is considered to be due to irreversible binding to gp120 rather than inhibition of reverse transcriptase or protease.
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PMID:Antiviral activity of natural and semi-synthetic chromone alkaloids. 753 92

The (alkylamino)piperidine bis(heteroaryl)piperizines (AAP-BHAPs) are a new class of human immunodeficiency virus type 1 (HIV-1)-specific inhibitors which were identified by targeted screening of recombinant reverse transcriptase (RT) enzymes carrying key nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-conferring mutations and NNRTI-resistant variants of HIV-1. Phenotypic profiling of the two most potent AAP-BHAPs, U-95133 and U-104489, against in vitro-selected drug-resistant HIV-1 variants carrying the NNRTI resistance-conferring mutation (Tyr->Cys) at position 181 of the HIV-1 RT revealed submicromolar 90% inhibitory concentration estimates for these compounds. Moreover, U-104489 demonstrated potent activity against BHA-P-resistant HIV-1MF harboring the Pro-236->Leu RT substitution and significantly suppressed the replication of clinical isolates of HIV-1 resistant to both delavirdine (BHAP U-90152T) and zidovudine. Biochemical and phenotypic characterization of AAP-BHAPresistant HIV-1IIIB variants revealed that high-level resistance to the AAP-BHAPs was mediated by a Gly-190->Glu substitution in RT, which had a deleterious effect on the integrity and enzymatic activity of virion-associated RT heterodimers, as well as the replication capacity of these resistant viruses.
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PMID:(Alkylamino) piperidine bis(heteroaryl)piperizine analogs are potent, broad-spectrum nonnucleoside reverse transcriptase inhibitors of drug-resistant isolates of human immunodeficiency virus type 1 (HIV-1) and select for drug-resistant variants of HIV-1IIIB with reduced replication phenotypes. 864 4

Selection of the IIIB strain of human immunodeficiency virus type (HIV-1) resistant to the (alkylamino)piperidine-bis(heteroaryl)piperazine (AAP-BHAP) U-104489 results in substitution of a glycine to glutamate at residue 190 (G190E) of reverse transcriptase (RT). The AAP-BHAP resistant HIV-1 displays reduced in vitro replication capacity [Olmsted, R. A., et. al. (1966) J. Virol. 70, 3698-3705]. We report here that the G190E mutation in recombinant heterodimeric HIV-1 RT, compared to the wild-type RT (G190) or a G190A control mutant, results in a 40% and 80% reduction in the polymerase and RNase H specific enzymatic activities, respectively. A primer-extension assay that allowed determination of DNA elongation by the G190E mutant RT on a heteropolymeric HIV-1 gag-based RNA template showed an overall decrease in DNA polymerization. The size distribution of products generated by G190E RT-associated RNase H digestion of RNA from [35S]poly(rA).poly(dT) was markedly distinct from that of the G190A RT and was consistent with the observed reduction in RT-associated RNase H activity of the G190E RT. When challenged with unlabeled substrates, the G190E RT was relatively nonprocessive with respect to DNA synthesis and RNA degradation. It is concluded that the deleterious effect of the G190E resistance mutation on both of these RT functions is most likely involved in the observed retarded replication capacity of the AAP-BHAP-(U-104489-) resistant HIV-1.
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PMID:A drug resistance mutation in the inhibitor binding pocket of human immunodeficiency virus type 1 reverse transcriptase impairs DNA synthesis and RNA degradation. 870 45

A novel class of bis(heteroaryl)piperazine (BHAP) analogs which possesses the ability to inhibit NNRTI (non-nucleoside reverse transcriptase inhibitor) resistant recombinant HIV-1 reverse transcriptase (RT) and NNRTI resistant variants of HIV-1 has been identified via targeted screening. Further investigation of the structure-activity relationships of close congeners of these novel (alkylamino)piperidine BHAPs (AAP-BHAPs) led to the synthesis of several compounds possessing the desired phenotype (e.g., activity against recombinant RTs carrying the Y181C and P236L substitutions). Further structural modifications were required to inhibit metabolism and modulate solubility in order to obtain compounds with the desired biological profile as well as appropriate pharmaceutical properties. The AAP-BHAPs with the most suitable characteristics were compounds 7, 15, and 36.
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PMID:Targeting delavirdine/atevirdine resistant HIV-1: identification of (alkylamino)piperidine-containing bis(heteroaryl)piperazines as broad spectrum HIV-1 reverse transcriptase inhibitors. 880 65

The major route of metabolism of the bis(heteroaryl)piperazine (BHAP) class of reverse transcriptase inhibitors (RTIs), atevirdine and delavirdine, is via oxidative N-dealkylation of the 3-ethyl- or 3-isopropylamino substituent on the pyridine ring. This metabolic pathway is also the predominant mode of metabolism of (alkylamino)piperidine BHAP analogs (AAP-BHAPs), compounds wherein a 4-(alkylamino)piperidine replaces the piperazine ring of the BHAPs. The novel AAP-BHAPs possess the ability to inhibit non-nucleoside reverse transcriptase inhibitor (NNRTI) resistant recombinant HIV-1 RT and NNRTI resistant variants of HIV-1. This report describes an approach to preventing this degradation which involves the replacement of the 3-ethyl- or 3-isopropylamino substituent with either a 3-tert-butylamino substituent or a 3-alkoxy substituent. The synthesis, bioactivity and metabolic stability of these analogs is described. The majority of analogs retain inhibitory activities in enzyme and cell culture assays. In general, a 3-ethoxy or 3-isopropoxy substituent on the pyridine ring, as in compounds 10, 20, or 21, resulted in enhanced stabilities. The 3-tert-butylamino substituent was somewhat beneficial in the AAP-BHAP series of analogs, but did not exert a significant effect in the BHAP series. Lastly, the nature of the indole substitution sometimes plays a significant role in metabolic stability, particularly in the BHAP series of analogs.
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PMID:Synthesis and bioactivity of novel bis(heteroaryl)piperazine (BHAP) reverse transcriptase inhibitors: structure-activity relationships and increased metabolic stability of novel substituted pyridine analogs. 897 55

The viral reverse transcriptase (RT) provides an attractive target in the search for anti-HIV therapies. The nonnucleoside inhibitors (NNIs) are a diverse set of compounds (usually HIV-1 specific) that function by distorting the polymerase active site upon binding in a nearby pocket. Despite being potent and of generally low toxicity, their clinical use has been limited by rapid selection for resistant viral populations. The 2.65-A resolution structure of the complex between HIV-1 RT and the bis(heteroaryl)piperazine (BHAP) NNI, 1-(5-methanesulfonamido-1H-indol-2-yl-carbonyl)-4- [3-(1-methyl-ethylamino) pyridinyl] piperazine (U-90152), reveals the inhibitor conformation and bound water molecules. The bulky U-90152 molecule occupies the same pocket as other NNIs, but the complex is stabilized quite differently, in particular by hydrogen bonding to the main chain of Lys-103 and extensive hydrophobic contacts with Pro-236. These interactions rationalize observed resistance mutations, notably Pro-236-Leu, which occurs characteristically for BHAPs. When bound, part of U-90152 protrudes into the solvent creating a channel between Pro-236 and the polypeptide segments 225-226 and 105-106, giving the first clear evidence of the entry mode for NNIs. The structure allows prediction of binding modes for related inhibitors [(altrylamino)piperidine-BHAPs] and suggests changes to U-90152, such as the addition of a 6 amino group to the pyridine ring, which may make binding more resilient to mutations in the RT. The observation of novel hydrogen bonding to the protein main chain may provide lessons for the improvement of quite different inhibitors.
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PMID:Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor. 910 91

Development of resistance to currently approved HIV therapies has continued to fuel research efforts to improve the metabolic stability and spectrum of activity of the (alkylamino)piperidine-containing bis(heteroaryl)piperazine (AAP-BHAP) class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). The synthesis of analogues in which the usual 3-alkylamino substituent on the pyridine ring is replaced by a 3-alkyl substituent led to compounds which retained activity against recombinant P236L and wild-type (WT) reverse transcriptase (RT), while inhibition of the Y181C mutant RT was reduced relative to the activity of the 3-alkylamino-substituted congeners. Testing of representative analogues in an in vitro liver microsome assay indicated that the alkyl substituent would not appreciably improve the metabolic stability of the AAP-BHAP template. In vivo pharmacokinetic evaluation of three compounds confirmed these results in that high systemic clearances were observed. Nevertheless, one compound (13), PNU-103657, possessed oral bioavailability in rats approaching that of the structurally related NNRTI drug delavirdine which is currently on the market for the treatment of HIV infection.
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PMID:Synthesis and structure-activity relationships of the (alkylamino)piperidine-containing BHAP class of non-nucleoside reverse transcriptase inhibitors: effect of 3-alkylpyridine ring substitution. 1051 84

Derivatives of piperidinylethyl, phenoxyethyl and fluoroethyl bromopyridyl thioureas were designed and synthesized as non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT). The anti-HIV activity of these compounds was examined by determining their ability to inhibit the replication of the HIV-1 strain HTLV(IIIB) in human peripheral blood mononuclear cells. The unsubstituted parent pyridyl thiourea compound N-[2-(1-piperidine)ethyl]-N'-[2-(pyridyl)] thiourea (1) exhibited no anti-HIV activity, even at 100 microM. However, the thiourea derivatives that contain a bromo- or chloro-substituted pyridyl group, compounds 2 and 5, inhibited HIV-1 replication at nanomolar concentrations. The addition of a methyl group onto the piperidine ring significantly altered the potency of these compounds; while methyl substitution at the 3-position of the piperidine ring reduced the activity, methyl substitution at the 2-position enhanced the anti-HIV activity. The IC50 value of the lead piperidinyl compound, N-[2-(2-methylpiperidinylethyl)]-N'-[2-(5-bromopyridyl)] thiourea (4) was <0.001 microM. All three phenoxyethyl derivatives, including the unsubstituted parent phenoxyethyl pyridyl thiourea compound N-[2-(phenoxy)ethyl]-N'-[2-(pyridyl)]thiourea (8) and the bromo-/chloro-substituted phenoxyethyl halopyridyl thiourea compounds N-[2-(phenoxy)ethyl]-N'-[2-(5-chloropyridyl)]thiourea (9) and N-[2-(phenoxy)ethyl]-N'-[2-(5-bromopyridyl)]thiourea (10) exhibited potent anti-HIV activity with nanomolar IC values. The corresponding fluoroethyl halopyridyl thiourea compounds beta-fluoro[2-phenethyl]-N'[2-(5-chloropyridyl)]thiourea (11) and beta-fluoro[2-phenethyl]-N'[2-(5-bromopyridyl)]thiourea (12) inhibited HIV-1 replication in PBMC with subnanomolar IC50 values and selectivity indices >30000. Compared to the corresponding phenoxyethyl thiourea compounds 9 and 10, these compounds were >4-5-fold more active as anti-HIV agents. Notably, the lead fluorothiourea compounds 11 and 12 were both substantially more active against the NNRTI-resistant HIV strains RT-MDR (V106A) and A17 (Y181C) than nevirapine or delavirdine. Taken together, our results provide additional experimental evidence that the structural features of the 'linker unit' between the pyridyl and phenyl moieties and changes in the phenyl group of PETT-related thiourea compounds significantly affects their biological activity as NNRTIs of HIV-1 RT.
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PMID:Piperidinylethyl, phenoxyethyl and fluoroethyl bromopyridyl thiourea compounds with potent anti-HIV activity. 1114 31

HIV entry within the cell involves the presence of at least two chemokine co-receptors, the CCR5 and CXCR4 receptors. Viral entry can be inhibited by the natural ligands for CXCR4, the CXC chemokine SDF-1 and CCR5, the CC chemokines RANTES, MIP-1alpha and MIP-1beta, respectively. Much research has been devoted ultimately to the development of small molecule chemokine antagonists that inhibit virus entry within the cell, and constitute in this way novel antiviral medications. The most potent and specific CXCR4 antagonists reported up to now are the bicyclam derivatives, which also potently block X4 HIV replication. One such compound, AMD3100 has proved to be a highly specific CXCR4 antagonist, which consistently blocks the outgrowth of all X4 HIV and dual-tropic (R5/X4) variants that use CXCR4 for entering the cells. From such bicyclam analogues, AMD3100 was selected as the clinical candidate, which, after initial Phase I studies, proceeded to Phase II trials, but unfortunately showed significant cardiac side effects which lead to its withdrawal from further development. The first nonpeptidic compound that interacts with CCR5, but not with CXCR4, is a quaternary ammonium derivative, TAK-779, which also shows potent but variable anti-HIV activity. A large number of potent CCR5 antagonists from several classes of polycyclic derivatives have been recently disclosed. Many such derivatives showed nanomolar binding affinity to the receptor, and at least one of them, the oxime-piperidine derivative SCH-351125 has progressed to clinical evaluation. The development of such agents for clinical use may constitute an additional approach for the treatment of HIV infection, in addition to the classical one involving reverse transcriptase and protease inhibitors.
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PMID:Non-peptidic chemokine receptors antagonists as emerging anti-HIV agents. 1242 Jul 52


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