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)

A series of benzothiadiazine derivatives were screened against the human immunodeficiency virus (HIV) and certain structure-activity relationships were defined for anti-HIV activity in this chemical class. The selected representative NSC 287474 was a highly potent inhibitor of HIV-induced cell killing and HIV replication in a variety of human cell lines, as well as in fresh human peripheral blood lymphocytes and macrophages. The compound was active against a panel of biologically diverse laboratory and clinical strains of HIV-1, including the AZT-resistant strain G910-6. However, the agent was inactive against HIV-2, and also against both nevirapine- and pyridinone-resistant strains (N119 and A17) of HIV-1, which are cross-resistant to several structurally diverse nonnucleoside reverse transcriptase inhibitors. The compound selectively inhibited HIV-1 reverse transcriptase, but not HIV-2 reverse transcriptase. Combination of NSC 287474 with AZT synergistically inhibited HIV-1-induced cell killing in vitro. The compound did not inhibit the replication of the Rauscher murine leukemia retrovirus or the simian immunodeficiency virus. The benzothiadiazine class of compounds represents a new active anti-HIV-1 chemotype within the diverse group of nonnucleoside reverse transcriptase inhibitors.
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PMID:Biological and biochemical anti-HIV activity of the benzothiadiazine class of nonnucleoside reverse transcriptase inhibitors. 752 14

Thiazolobenzimidazole (NSC 625487) was a highly potent inhibitor of human immunodeficiency virus-induced cell killing and viral replication in a variety of human cell lines, as well as fresh human peripheral blood lymphocytes and macrophages. The compound was active against a panel of biologically diverse laboratory and clinical strains of HIV-1, including the AZT-resistant strain G910-6. However, the agent was inactive against HIV-2 and a pyridinone-resistant strain (A17) of HIV-1, a strain which is cross-resistant to several structurally diverse members of a common pharmacologic class of nonnucleoside reverse transcriptase inhibitors. The compound selectively inhibited HIV-1 reverse transcriptase but not HIV-2 reverse transcriptase. Combinations of thiazolobenzimidazole with either AZT or ddI synergistically inhibited HIV-1 induced cell killing in vitro. Thiazolobenzimidazole also inhibited the replication of the Rauscher murine leukemia retrovirus. Thus, thiazolobenzimidazole is a new active anti-HIV-1 chemotype and may represent a subclass of nonnucleoside reverse transcriptase inhibitors with an enhanced range of anti-retroviral activity.
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PMID:Thiazolobenzimidazole: biological and biochemical anti-retroviral activity of a new nonnucleoside reverse transcriptase inhibitor. 769 15

The conformation of the last 201 nucleotides located at the 3'-end of brome mosaic virus (BMV) RNAs was investigated in solution using different chemical and enzymatic probes. Bases were probed with dimethylsulfate (which methylates N-1 positions of A, N-3 positions of C and N-7 positions of G), a carbodiimide (which modifies N-1 positions of G and N-3 positions of U) and diethylpyrocarbonate (which modifies N-7 positions of A). Ribonucleases T1, U2 and S1 were used to map unpaired nucleotides and ribonuclease V1 to monitor paired bases or stacked nucleotides. Cleavage or modification sites were detected by gel electrophoresis either indirectly by analyzing DNA sequence patterns generated by primer extension with reverse transcriptase of the modified RNAs or by direct identification within the statistical cleavage patterns of the RNA. On the basis of these biochemical results, an atomic model was built by computer modeling and its stereochemistry refined. The deduced secondary structure of the RNA confirms data previously proposed by others but contains additional base-pairs (A27-U32, A28-G31, G41-A134, G64-C68, U80-A99, G81-A98, G88-U91, G100-U126, U104-U125, G162-G166 and A172-A191), one new tertiary long-range interaction (U103-U164) and a small triple helical conformation with (G41-A134)-A18 and (C42-G133)-A17 interactions. The new secondary structure also indicates the existence of a second pseudoknot involving pairing between residues A181 to A184 and residues U197 to U194, outside the domain conferring tyrosylation ability to BMV RNA. The main outcome from the model stems from its intricate folding, which allows a new assignment for the domains mimicking the anticodon- and D-loop regions of tRNA. Interestingly, the stem and loop region found structurally to be analogous to the anticodon arm of tRNA(Tyr) does not contain the tyrosine anticodon involved in the aminoacylation process. The structural analogies with canonical tRNA(Tyr) illustrate the functional mimicry existing between the BMV RNA structure and canonical tRNA(Tyr) that allows for their efficient aminoacylation by tyrosyl-tRNA synthetase. This structural model rationalizes mutagenic and footprinting data that have established the importance of specific regions of the viral RNA for recognition by its replicase, (ATP,CTP):tRNA nucleotidyl-transferase and yeast tyrosyl-tRNA synthetase. The new fold has biological implications that can be used as a predictive tool for elaborating new experiments.
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PMID:Solution structure of the 3'-end of brome mosaic virus genomic RNAs. Conformational mimicry with canonical tRNAs. 828 79

The novel thiourea compound N-[2-(2,5-dimethoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thi ourea (HI-236) targeting the non-nucleoside inhibitor (NNI) binding pocket of HIV-1 reverse transcriptase (RT) was rationally designed using a computer model of the NNI binding pocket. The NNI binding pocket model takes into consideration changes in binding pocket size, shape, and changes in residue character that result from clinically-observed NNI resistance-associated mutations of HIV RT. RT assays revealed that HI-236 was not only more potent than trovirdine, MKC-442, and AZT against the drug-sensitive HIV-1 strain HTLV(IIIB), it was also 50-100 times more effective than delavirdine or nevirapine and twice as effective as our recently reported lead compound N-[2-(2-fluorophenethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (HI-240) against the NNI-resistant Y181C mutant HIV-1 strain A17. Most importantly, HI-236 was highly effective against the multidrug-resistant HIV-1 strain RT-MDR with multiple mutations involving the RT residues 74V, 41L, 106A, and 215Y. The activity of HI-236 against RT-MDR was superior to that of other anti-HIV agents tested, which are listed in the following order: HI-236 (IC50: 5 nM) > HI-240 (IC50: 6 nM) > trovirdine (IC50: 20 nM) > AZT (IC50: 150 nM) > MKC-442 (IC50: 300 nM) > delavirdine (IC50: 400 nM) > nevirapine (IC50: 5 microM).
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PMID:Rational design of N-[2-(2,5-dimethoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (HI-236) as a potent non-nucleoside inhibitor of drug-resistant human immunodeficiency virus. 1038 42

A computer model of reverse transcriptase (RT) from human immunodeficiency virus type 1 (HIV-1) was used to design thiourea compounds that were predicted to inhibit RT. The RT model was used to approximate how changes in binding pocket shape, volume and chemical properties resulting from residue mutations would affect inhibitor binding. Our lead compound, N-[2-(2,5-dimethoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thi ourea (HI-236) was tested against clinically observed non-nucleoside inhibitor (NNI)-resistant mutated strains of HIV. HI-236 was more potent than trovirdine, MKC-442 and zidovudine against the drug-sensitive HIV-1 strain IIIB, 50-100 times more effective than delavirdine or nevirapine and twice as effective as our recently reported lead compound N-[2-(2-fluorophenethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (HI-240) against the NNI-resistant Y181C mutant HIV-1 strain A17. HI-236 was highly effective against the multidrug-resistant HIV-1 strain RT-MDR containing multiple mutations involving the RT residues 74V, 41L, 106A and 215Y. In general, thiourea compounds such as HI-236 and HI-240 showed better inhibition of drug-resistant strains of HIV-1 than thioalkylbenzyl-pyrimidine compounds such as HI-280 and HI-281. The improved activity of thioureas against RT mutants is consistent with a structural analysis of the NNI binding pocket model of RT. The activity of HI-236 against RT-MDR was superior to that of other anti-HIV agents tested, in the following order, from high to low activity; HI-236 (IC50 5 nM), HI-240 (IC50 6 nM), trovirdine (IC50 20 nM), zidovudine (IC50 150 nM), MKC-442 (IC50 300 nM), delavirdine (IC50 400 nM) and nevirapine (IC50 5 microM).
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PMID:Structure-based design of non-nucleoside reverse transcriptase inhibitors of drug-resistant human immunodeficiency virus. 1057 78

The composite non-nucleoside reverse transcriptase inhibitor (NNRTI) binding pocket model was used to study a number of thiourea analogues with different substitutions at the 4-phenyl position including N-[2-(4-methylphenyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (compound HI-244), which inhibited recombinant RT better than trovirdine or compound HI-275 with an unsubstituted phenyl ring. HI-244 effectively inhibited the replication of HIV-1 strain HTLV(IIIB) in human peripheral blood mononuclear cells with an IC50 value of 0.007 microM, which is equal to the IC50 value of trovirdine. Notably, HI-244 was 20 times more effective than trovirdine against the multidrug-resistant HIV-1 strain RT-MDR with a V106A mutation (as well as additional mutations involving the RT residues 74V, 41L and 215Y) and seven times more potent than trovirdine against the NNRTI-resistant HIV-1 strain A17 with a Y181C mutation.
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PMID:N-[2-(4-methylphenyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea as a potent inhibitor of NNRTI-resistant and multidrug-resistant human immunodeficiency virus type 1. 1081 37

Chiral derivatives of two cyclohexylethyl halopyridyl thiourea compounds (HI-509 and HI-510), two alpha-methyl benzyl halopyridyl compounds (HI-511 and HI-512), and a cyclohexyl ethyl thiazolyl thiourea compound (HI-513) were synthesized as nonnucleoside inhibitors (NNI) of human immunodeficiency virus (HIV) reverse transcriptase (RT). The R stereoisomers of all five compounds inhibited the recombinant RT in vitro with 100-fold lower IC50 values. HI-509R, HI-510R, HI-511R, HI-512R and HI-513R were active anti-HIV agents and inhibited HIV-1 replication in human peripheral blood mononuclear cells at nanomolar concentrations, whereas their enantiomers were inactive. Each of these five compounds was also active against NNI-resistant HIV-1 strains, with HI-511R being the most active agent. When tested against the NNI-resistant HIV-1 strain A17 with a Y181C mutation in RT, HI-511R was found to be 10,000-times more active than nevirapine, 5000-times more active than delavirdine, and 50-times more active than trovirdine. HI-511 R inhibited the HIV-strain A17 variant, containing RT mutations Y181C plus K103N, with an IC50 value of 2.7 microM, whereas the IC50 values of nevirapine, delavirdine, and trovirdine against this highly NNI-resistant HIV-1 strain were >100 microM.
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PMID:Stereochemistry of halopyridyl and thiazolyl thiourea compounds is a major determinant of their potency as nonnucleoside inhibitors of HIV-1 reverse transcriptase. 1099 73

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

Several thiazolyl thiourea derivatives were designed and synthesized as non-nucleoside inhibitors (NNRTI) of HIV-1 reverse transcriptase. Six lead compounds were identified that showed subnanomolar IC50 values for the inhibition of HIV replication, were minimally toxic to human peripheral blood mononuclear cells (PBMC) with CC50 values ranging from 28 to >100 microM, and showed remarkably high selectivity indices ranging from 28,000 to >100,000. The most promising compound was N-[1-(1-furoylmethyl)]-N'-[2-(thiazolyl)]thiourea (compound 6), which showed potency against two NNRTI-resistant HIV-1 isolates (A17 and A17 variant) at nanomolar to low micromolar concentrations, exhibited much greater potency against both wild-type as well as NNRTI-resistant HIV-1 than nevirapine, delavirdine, HI-443, and HI-244, was minimally toxic to PBMC, and had a selectivity index of > 100,000. The potency and minimal cytotoxicity of these aromatic/heterocyclic thiourea compounds suggest that they may be potentially useful as anti-AIDS drugs.
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PMID:Anti-HIV activity of aromatic and heterocyclic thiazolyl thiourea compounds. 1122 62

Systematic simplification of the molecular structures of epicatechin gallate and epigallocatechin gallate to determine the minimum structural characteristics necessary for HIV-1 reverse transcriptase inhibition in vitro resulted in several compounds that strongly inhibited the native as well as the A17 double mutant (K103N Y181C) enzyme, which is normally insensitive to most known nonnucleoside inhibitors.
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PMID:Simplified catechin-gallate inhibitors of HIV-1 reverse transcriptase. 1159 19


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