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)

An A ring-secocycloartene triterpenoid, nigranoic acid (3,4-secocycloarta-4(28),24-(Z)-diene-3,-26-dioic acid, (1) was isolated from the stems of Schisandra sphaerandra, a Chinese traditional medicinal plant. Its structure elucidation and unambiguous NMR spectral assignment were achieved by the combination of 1D- and 2D-NMR techniques with the aid of computer modeling. Nigranoic acid showed activity in several anti-HIV reverse transcriptase and polymerase assays.
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PMID:Nigranoic acid, a triterpenoid from Schisandra sphaerandra that inhibits HIV-1 reverse transcriptase. 877 43

The three-dimensional solution structure of the hybrid-chimeric duplex r(gcca)d(CTGC).d(GCAGTGGC) has been determined by two-dimensional NMR, restrained molecular dynamics (rMD), and NOE back-calculation methods. This chimera, consisting of a chimeric RNA-DNA strand and its complementary DNA strand, is formed after priming (-)-strand DNA synthesis by tRNA(Lys3) and subsequent (+)-strand DNA synthesis by reverse transcriptase and is an obligatory intermediate in the formation of double-stranded DNA prior to HIV-1 retrovirus integration. The duplex consists of two different types of double helix: a hybrid form (H-form) and a B-form structure connected by a junction. It is chemically similar to several other Okazaki fragments whose structures have been previously determined in our laboratory. However, some structural parameters are not the same and were found to be sequence dependent. In particular, the sugar conformations at the DNA base pair proximal to the hybrid segment vary from O4'-endo to C2'-endo depending on the base composition. The position of the transition from the relatively wide groove of H-form to the narrow groove of B-form is also sequence dependent, occurring either exactly at the RNA-DNA junction or within the purely DNA segment of the chimera-as is the case in the structure of the present HIV-1 (-)-strand primer. This structural change produces a kink at the DNA-DNA step adjacent to the RNA-DNA junction in the HIV-1 (-)-strand primer. The sequence dependence of structures of RNA-DNA chimeric duplexes may be responsible for the variable cleavage pattern of different Okazaki fragments by reverse transcriptase RNase H.
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PMID:Structural variation among retroviral primer-DNA junctions: solution structure of the HIV-1 (-)-strand Okazaki fragment r(gcca)d(CTGC).d(GCAGTGGC). 878 May 9

The 1-(2',6'-difluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazole (L), a highly potent nonnucleoside HIV-1 reverse transcriptase inhibitor, has been reacted with [Pd2Cl4(PPr3n)2] in order to study its coordinating properties towards metal ions. The structure of the synthesized product has been examined in solution by 1H and 13C NMR, and in solid by X-ray analysis. [Pd(PPr3n)(L)Cl2] has a trans structure and L coordinates through imine nitrogen. The loss of anti-HIV properties of L, by complexation, suggests that, unless biological inactivation is simple due to steric reasons, the imine nitrogen atom is an active site of the molecule.
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PMID:Synthesis and characterization in solid and solution of trans-dichloro-1-(2', 6'-difluorophenyl)-1H,3H-thiazolo [3,4-a]-benzimidazole(tri-n-propyl-phosphine)-palladium(II)": a palladium(II) complex of a ligand with anti-HIV properties. 901 42

Transfer RNA(Lys)SUU, with a 5-modified-2-thiouridine at wobble position 34, facilitates -1 frameshifts for correct translation of the Escherichia coli DNA polymerase gamma subunit and retroviral polymerases. Peptidyl-tRNA(Lys)SUU prematurely terminates translation more often than other tRNAs. In order to determine if the anticodon structures of bacterial and mammalian tRNA(Lys)SUU species explain these observations, oligonucleotides corresponding to the anticodon regions of mammalian and E. coli tRNA(Lys)SUU were synthesized and their physicochemical properties compared with that of E. coli tRNA(Glu)SUC. The anticodon region of tRNA(Lys)SUU was stabilized by an unusual interaction between the side chains of the 5-modified-s(2)U34 and N-6-threonylcarbamoyl-adenosine-37 (t(6)A37), a combination of modified nucleosides unique to tRNA(Lys)SUU species. This first observation of modified nucleoside side-chain interactions is analogous to the interactions of amino acid side chains in proteins. The tRNA(Lys)SUU anticodon structure was determined from NMR restraints on model oligonucleotides. With only two of three anticodon bases available for codon pairing, this unconventional anticodon structure is a reasonable explanation for the bacterial and mammalian tRNA(Lys)SUU tendency to frameshift. A two-out-of-three reading of coding triplets also explains the increased rate at which peptidyl-tRNA(Lys)SUU prematurely terminates translation. In addition, modified nucleoside interaction distorts the anticodon loop. The distorted loop is a possible structural determinant for the preferential selection of tRNA(Lys3)SUU as primer of HIV-1 reverse transcriptase in vivo.
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PMID:Unconventional structure of tRNA(Lys)SUU anticodon explains tRNA's role in bacterial and mammalian ribosomal frameshifting and primer selection by HIV-1. 908 48

The roots of Ononis spinosa subsp. leiosperma (Leguminosae) afforded a new glycoside, spinonin (1), possessing a novel skeleton, in addition to the known isoflavonoid glycoside, ononin [7beta-(glucosyloxy)formononetin] (2) and the known pterocarpan, 7-demethoxy-7-D-(glucosyloxy)homopterocarpin (3). The structure of the new isolate was elucidated by spectral methods including 1H and 13C NMR, COSY, APT, HETCOR, HMBC, NOESY, CD, FABMS, HRMS, EIMS, CIMS, and some chemical reactions. Spinonin was inactive against a number of human cancer cell lines and HIV-1 reverse transcriptase. The compounds 1 and 3 showed weak activity against Pseudomonas aeruginosa, whereas 2 was active against beta-hemolytic Streptococcus.
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PMID:Spinonin, a novel glycoside from Ononis spinosa subsp. leiosperma. 918 26

Delavirdine mesylate (U-90152T) is a highly specific nonnucleoside HIV-1 reverse transcriptase inhibitor currently under development for the treatment of AIDS. The metabolism of delavirdine was investigated in male and female cynomolgus monkeys after oral administration of [14C-carboxamide]delavirdine mesylate at single doses of 80 mg/kg and multiple doses of 160 to 300 mg/kg/day. Desalkyl delavirdine was the major metabolite in circulation. In urine, desalkyl delavirdine accounted for nearly half of the radioactivity, with despyridinyl delavirdine and conjugates of desalkyl delavirdine accounting for most of the remaining radioactivity. Bile was mostly composed of desalkyl delavirdine and 6'-O-glucuronide delavirdine, with parent drug, 4-O-glucuronide delavirdine, and conjugates of desalkyl delavirdine as significant components. In addition, several minor metabolites were observed in urine and bile of delavirdine treated monkeys. The metabolism of delavirdine in the monkey was extensive and involved N-desalkylation, hydroxylation at the C-4' and C-6' positions of the pyridine ring, hydroxylation at the C-4 position of the indole ring, pyridine ring-cleavage, N-glucuronidation of the indole ring, and amide bond cleavage as determined by MS and/or one-dimensional and two-dimensional NMR spectroscopies. Phase II biotransformations included glucuronidation, sulfation, and beta-N-acetylglucosaminidation. The identification of the N-linked beta-N-acetylglucosamine and 4-O-glucuronide metabolites of delavirdine represents novel biotransformation pathways.
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PMID:Identification of the metabolites of the HIV-1 reverse transcriptase inhibitor delavirdine in monkeys. 922 76

Delavirdine mesylate (U-90152T) is a highly specific nonnucleoside HIV-1 reverse transcriptase inhibitor currently under development for the treatment of AIDS. The excretion, disposition, brain penetration, and metabolism of delavirdine were investigated in CD-1 mice after oral administration of [14C]delavirdine mesylate at single doses of 10 and/or 250 mg/kg and multiple doses of 200 mg/kg/day. Studies were conducted with 14C-carboxamide and 2-14C-pyridine labels, as well as 13C3-labeled drug to facilitate metabolite identification. Excretion was dose dependent with 57-70% of the radioactivity eliminated in feces and 25-36% in urine. Pharmacokinetic analyses of delavirdine and its N-desisopropyl metabolite (desalkyl delavirdine) in plasma showed that delavirdine was absorbed and metabolized rapidly, that it constituted a minor component in circulation, that its pharmacokinetics were nonlinear, and that its metabolism to desalkyl delavirdine was capacity limited or inhibitable. Delavirdine did not significantly cross the blood-brain barrier; however, its N-isopropylpyridinepiperazine metabolite arising from amide bond cleavage-was present in brain at levels 2- to 3-fold higher than in plasma. The metabolism of delavirdine in the mouse was extensive and involved amide bond cleavage, N-desalkylation, hydroxylation at the C-6' position of the pyridine ring, and pyridine ring-cleavage as determined by MS and/or 1H and 13C NMR spectroscopies. N-desalkylation and amide bond cleavage were the primary metabolic pathways at low drug doses and, as the biotransformation of delavirdine to desalkyl delavirdine reached saturation or inhibition, amide bond cleavage became the predominant pathway at higher doses and after multiple doses.
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PMID:Metabolism of the HIV-1 reverse transcriptase inhibitor delavirdine in mice. 922 77

The anticodon stem-loop hairpin of tRNA(Lys,3) was synthesized and the solution structure determined by NMR spectroscopy. The hairpin is thermodynamically stabilized by pseudouridine as determined by UV Tm measurements, and the local loop structure is stabilized with base-stacking of the nucleosides in the anticodon loop 5' of the psi 39 nucleoside modification. The tRNA(Lys,3) hairpin also contains an A(+)-C base-pair that effectively reduces the size of the normal 7 nucleotide anticodon loop to 5 nucleotides and induces a change in the loop backbone conformation. The stabilizing effects of the A(+)-C base-pair and pseudouridine are only partially additive, suggesting that the conformational changes caused by each modification are not completely compatible. The structure of the anticodon loop is distinctly different from that seen for other tRNAs exemplified by tRNA(Phe), suggesting that the full complement of modified nucleosides present in tRNA(Lys,3) should significantly change the structure compared to the unmodified tRNA anticodon loop. The conformation of the loop has important implications for the role of nucleoside modification in codon-anticodon recognition and for utilization of tRNA(Lys,3) by HIV-1 as the natural reverse transcriptase primer.
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PMID:The effect of pseudouridine and pH on the structure and dynamics of the anticodon stem-loop of tRNA(Lys,3). 947 5

The Gag-encoded nucleocapsid protein NCp7 (72 amino acids) from HIV-1, the regulatory protein, Vpr (96 amino acids) and numerous derivatives have been synthesized by solid phase method and their structures determined by 2D NMR. In NCp7, the two highly folded zinc fingers of the Cx2Cx4Hx4C type are in close spacial proximity and the replacement of H by C in the first zinc finger or P by L in the short interdigital domain led to structural modifications evidenced by NMR. In vivo, these point mutations induced a complete loss of viral infectivity by interrupting critical step(s) of the retroviral life cycle. To account for these findings, a model of the complex between NCp7 and d (ACGCC) has been proposed from NMR data, showing the intercalation of Trp37 in the oligonucleotide. This model could also explain the role of NCp7 in the formation of viral particles and agrees with the modifications in morphology of the virions containing mutations in the NCp7 zinc fingers. Vpr is essentially constituted by two long helical domains at its N- and C-terminals and the side chains of Leu60 and Leu67 participate in a leucine-zipper mode of intramolecular interaction. The results obtained have been used to try to develop new antiviral agents inhibiting NCp7 functions and thus possibly devoid of the resistance effects found with inhibitors of HIV enzymes (reverse transcriptase and protease).
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PMID:Structure, biological functions and inhibition of the HIV-1 proteins Vpr and NCp7. 947 50

The preparation and examination of 2-22 constituting a systematic study of the chromophore of sandramycin (1) are detailed. Fluorescence quenching studies were used to establish binding constants for 1-24 within calf thymus DNA, within a single high affinity bis-intercalation binding site 5'-d(GCATGC)2, and to establish the preference for sandramycin binding to 5'-d(GCXXGC)2 where XX = AT, TA, GC, and CG. From the latter studies, sandramycin was found to exhibit a preference that follows the order: 5'-d(GCATGC)2 > 5'-d(GCGCGC)2, deltadeltaGo = 0.3kcal/mol > 5'-d(GCTAGC)2, 5'-d(GCCGGC)2, deltadeltaGo = 0.6 kcal/mol although it binds with high affinity to all four deoxyoligonucleotides. The two highest affinity sequences constitute repeating 5'-PuPy motifs with each intercalation event occurring at a 5'-PyPu step. The most effective sequence constitutes the less stable duplex, contains the sterically most accessible minor groove central to the bis-intercalation site, and the ability to accept two gly-NH/TC2 carbonyl H-bonds identified in prior NMR studies. Similarly, the contribution of the individual structural features of the chromophore were assessed with the high affinity duplex sequence 5'-d(GCATGC)2. To a first approximation, the cytotoxic properties were found to parallel trends established in the DNA binding affinities. The exception to this generalization was 4 which lacks the sandramycin chromophore phenol. Although typically 4-10x less potent than sandramycin against leukemia cell lines, it proved to be 1-10,000x more potent against melanomas, carcinomas, and adenocarcinomas exhibiting IC50 values of 1 pM-10 nM placing it among the most potent agents identified to date. Additionally, the first disclosure of the HIV-1 reverse transcriptase inhibitory activity of sandramycin (1) as well as that of its key analogs are described and define the chromophore structural features required for their exceptional potency. Two analogs, 18 and 3, roughly maintain the HIV-1 reverse transcriptase inhibitory potency of 1 but exhibit substantially diminished cytotoxic activity (10(2)-10(3)x).
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PMID:Synthesis of key sandramycin analogs: systematic examination of the intercalation chromophore. 950 8


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