Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Beta-D and beta-L-enantiomers of 2',3'-dideoxycytidine analogues are potent chain-terminators and antimetabolites for viral and cellular replication. Seemingly small modifications markedly alter their antiviral and toxicity patterns. This review discusses previously published and recently obtained data on the effects of 5- and 2'-fluorine substitution on the pre-steady state incorporation of 2'-deoxycytidine-5'-monophosphate analogues by HIV-1 reverse transcriptase (RT) in light of their biological activity. The addition of fluorine at the 5-position of the pyrimidine ring altered the kinetic parameters for all nucleotides tested. Only the 5-fluorine substitution of the clinically relevant nucleosides (-)-beta-L-2',3'-dideoxy-3'-thia-5-fluorocytidine (L-FTC, Emtriva), and (+)-beta-D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine (D-D4FC, Reverset), caused a higher overall efficiency of nucleotide incorporation during both DNA- and RNA-directed synthesis. Enhanced incorporation by RT may in part explain the potency of these nucleosides against HIV-1. In other cases, a lack of correlation between RT incorporation in enzymatic assays and antiviral activity in cell culture illustrates the importance of other cellular factors in defining antiviral potency. The substitution of fluorine at the 2' position of the deoxyribose ring negatively affects incorporation by RT indicating the steric gate of RT can detect electrostatic perturbations. Intriguing results pertaining to drug resistance have led to a better understanding of HIV-1 RT resistance mechanisms. These insights serve as a basis for understanding the mechanism of action for nucleoside analogues and, coupled with studies on other key enzymes, may lead to the more effective use of fluorine to enhance the potency and selectivity of antiviral agents.
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PMID:Probing the mechanistic consequences of 5-fluorine substitution on cytidine nucleotide analogue incorporation by HIV-1 reverse transcriptase. 1452 28

To decrease the toxicity of potent anti-HIV nucleosides 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-dideoxy-3'-fluorothymidine (3'-FddThd, FLT), their new analogues, 3'-azido-2',3'-dideoxy-5-hydroxymethyluridine (3'-Az5HmddUrd) and 2',3'-dideoxy-3'-fluoro-5-hydroxymethyluridine (3'-F5HmddUrd), were synthesized. The reaction of 3'-azido-2',3'-dideoxyuridine (3'-AzddUrd) and 2',3'-dideoxy-3'-fluorouridine (3'-FddUrd) with formaldehyde, under strongly alkaline conditions and at elevated temperature, proceeded after 4 days to completion to afford the corresponding 5-hydroxymethyl derivatives 3'-Az5HmddUrd and 3'-F5HmddUrd in good yield. These compounds were also prepared by oxidation of AZT and FLT with the use of K2S2O8. 1H NMR analyses were subjected to the series of 3', 4 and 5-substituted pyrimidine 2'-deoxy- and 2',3'-dideoxynucleosides involving 3'-Az5HmddUrd and 3'-F5HmddUrd. Analysis of the sugar furanose ring puckering demonstrated that all 3'-fluorine derivatives exhibited strong domination of the S conformation (approximately 100%) while 3'-substitution by electron-donating groups, such as NH2, increased population of the N conformation. Experimentally observed substituent effect on the furanose ring puckering equilibrium was reconstructed in the 100 ps molecular dynamic trajectories obtained for AZT, FLT, dThd, 2',3'-ddThd and 3'-amino-2',3'-ddThd. It may be concluded that anti-HIV activity is linked to a direct interaction of the 3'-substituent with reverse transcriptase (RT) binding site. Anti-HIV activities of 3'-Az5HmddUrd and 3'-F5HmddUrd are lower than activity of AZT and FLT; however, 3'-Az5HmddUrd and 3'-F5HmddUrd are less toxic than AZT and FLT.
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PMID:Synthesis, solution conformation and anti-HIV activity of novel 3'-substituted-2',3'-dideoxy-5-hydroxymethyluridines and their 4,5-substituted analogues. 1452 29

[1'-Fluoro-2',2'-bis-(hydroxymethyl)cyclopropylmethyl]purines were designed, synthesized and their antiviral activity against poliovirus, HSV and HIV was evaluated.
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PMID:Synthesis of [1'-fluoro-2',2'-bis-(hydroxymethyl)cyclopropylmethyl]purines as antiviral agents. 1456 20

In order to find out the possible role of fluorine substituent in binding of the fluorinated cytidine analogues at the active site of HIV-1 RT, binding modes of several 5-fluoro cytidine analogues, such as FTC, D-dioxolane 5-FC and D-2'F-d4FC to the active site of HIV-1 reverse transcriptase, were compared by molecular dynamics studies.
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PMID:Effects of fluorine substitution of cytosine analogues on the binding affinity to HIV-1 reverse transcriptase. 1469 76

Comparison of the active sites of the human HIV-1 reverse transcriptase (RT) and the homology-modelled hepatitis B virus (HBV) polymerase shows that the active sites of both enzymes are open to L-nucleosides, but the position where the 3'-substituent of the L-ribose projects in HBV polymerase is wider and deeper than HIV-1 RT, which enables the HBV polymerase to accommodate various 3'-substituted L-nucleosides. However, the space is not sufficient to accommodate a bulky 3'-substituent such as the 3'-azido group of L-3'-azido-3'-deoxythymidine. Analysis of the minimized structure of rtM204V HBV polymerase/3TCTP complex shows that, instead of the steric stress produced by rtV204, a loss of the van der Waals contact around the oxathiolane sugar moiety of 3TCTP caused by the mutation results in the disruption of the active site. Therefore, nucleosides, which are stabilized by additional specific interaction with the enzyme residues, can have more opportunities to circumvent the destabilization by the loss of hydrophobic interaction conferred by mutation. Specifically, the substitution at the 3'-position would be beneficial as the HBV polymerase has wide open space composed of the highly conserved motif (YMDD) where the 3'-substituents of the L-nucleosides project. As an example, our study shows that the 3'-fluorine atom contributes to the antiviral activity of L-3'-Fd4CTP against rtM204V HBV polymerase by readily compensating for the loss of the van der Waals interaction around the 2',3'-double bond through a formation of a hydrogen bond to the amide backbone of rtD205.
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PMID:Mechanism of antiviral activities of 3'-substituted L-nucleosides against 3TC-resistant HBV polymerase: a molecular modelling approach. 1496 37

Various D- and L-2',3'-unsaturated 3'-fluoro-4'-thionucleosides (D- and L-3'F-4'Sd4Ns) were synthesized for the studies of structure-activity relationships. The synthesized D-2',3'-unsaturated 3'-fluoro-4'-thionucleosides did not show any significant antiviral activity against HIV-1, while unnatural L-nucleosides such as cytosine 34 (EC(50) = 0.13 microM; EC(90) = 1.7 microM) and 5-fluorocytosine 35 (EC(50) = 0.031 microM; EC(90) = 0.35 microM) derivatives exhibited potent anti-HIV activity without significant toxicity. Molecular modeling study shows that the 3'-fluorine atom of the d-2',3'-unsaturated cytidine triphosphate (D-3'F-4'Sd4CTP) experiences unfavorable electrostatic interaction with its own triphosphate moiety, resulting in the decreased binding affinity to wild-type HIV-1 reverse transcriptase (RT), which may be one of the reasons for the insensitivity of HIV-1 RT to these compounds. On the other hand, L-3'F-4'Sd4CTP binds to the active site of wild-type HIV-1 RT without steric hindrance and there is a possible hydrogen bonding between the 3'-fluorine atom and Asp185, which correlates with its potent anti-HIV activity. However, L-3'F-4'Sd4C 34 and L-3'F-4'Sd4FC 35 showed high cross-resistance to 3TC-resistant mutant (M184V) RT. Like other unnatural L-nucleosides, the unfavorable steric hindrance of the sugar moiety of L-3'F-4'Sd4CTP with the side chain of Val184 explains its significant cross-resistance to the M184V mutant.
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PMID:Synthesis, structure-activity relationships, and mechanism of drug resistance of D- and L-beta-3'-fluoro-2',3'-unsaturated-4'-thionucleosides as anti-HIV agents. 1502 54

A series of 5-(trifluoroethoxymethyl)-2',3'-dideoxyuridines and 5-[bis(trifluoroethoxy)-methyl]-2',3'-dideoxyuridines have been prepared and screened for antiviral activity. The conformations of these compounds are discussed on the bases of NOE studies and the MO calculations. Modelling and NOE studies suggest both syn- and anti conformations for these 5-(2,2,2-trifluoroethoxymethyl)- and 5-[bis(2,2,2-trifluoroethoxy)-methyl]- derivatives. The NOE parameters are also suggested to be more attributable to the nature of the fluorine atom than to structural or conformational changes. Compounds 17, 26 and 30 showed some activity in anti-HIV-1 and anti-HIV-2 assays, but the compounds were devoid of activity against HSV and human rhinovirus. The compounds tested exhibited low cytotoxicity and were inactive against a bank of cancer cells in vitro.
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PMID:Synthesis and antiviral activity of novel fluorinated 2',3'-dideoxynucleosides. 1504 33

Quinolones represent an important class of broad-spectrum antibacterials, the main structural features of which are a 1,4 dihydro-4-oxo-quinolinyl moiety bearing an essential carboxyl group at position 3. Quinolones inhibit prokaryotic type II topoisomerases, namely DNA gyrase and, in a few cases, topoisomerase IV, through direct binding to the bacterial chromosome. Based on the hypothesis that these drugs could also bind to the viral nucleic acids or nucleoprotein-complexes, several quinolone derivatives were tested for their antiviral activity. Indeed, antibacterial fluoroquinolones were shown to be effective against vaccinia virus and papovaviruses; these preliminary results prompted the synthesis of modified quinolones to optimize antiviral action and improve selectivity index. The introduction of an aryl group at the piperazine moiety of the fluoroquinolone shifted the activity from antibacterial to antiviral, with a specific action against HIV. The antiviral activity seemed to be related to an inhibitory effect at the transcriptional level, and further evidence suggested a mechanism of action mediated by inhibition of Tat functions. Substitution of the fluorine at position 6 with an amine group to give aryl-piperazinyl-6-amino-quinolones improved the activity and selectivity against HIV-1: the most potent compound of this series was shown to inhibit virus replication through interference with Tat-TAR interaction. A comprehensive SAR investigation was performed based on additional chemical intervention to the quinolone template moiety, such as the introduction of nucleoside derivative functions. The information gained so far will be useful for future rational drug design aimed at developing new compounds with optimized antiviral activity.
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PMID:Antiviral properties of quinolone-based drugs. 1518 Apr 59

Our recent studies demonstrated that d- and l-2'-fluoro-2',3'-unsaturated nucleosides (d- and l-2'-F-d4Ns) display moderate to potent antiviral activities against HIV-1 and HBV. As an extension of these findings, beta-d-3'-fluoro-2',3'-unsaturated nucleosides were synthesized as potential antiviral agents. The key intermediate (2S)-5-(1,3-dioxolan)-1-benzoyloxy-3,3-difluoropentan-2-ol 6 was prepared from 2,3-O-isopropylidene-d-glyceraldehyde 1, which was converted to 5-O-benzoxy-d-2-deoxy-3,3-difluoropentofuranosyl acetate 7 by the ring-closure reaction under acidic conditions. The acetate 7 was condensed with silylated purine and pyrimidine bases, which produced the alpha and beta isomers. The 3',3'-difluoro nucleosides were then treated with t-BuOK to give the desired 3'-fluoro-unsaturated nucleosides. We studied the structure-activity relationships of d-3'-fluoro-2',3'-unsaturated nucleosides against HIV-1 in human peripheral blood mononuclear cells, from which we found that the cytosine derivative 26 was the most potent among the synthesized compounds. To understand the mode of action and drug resistance profile, with particular regard to the role of fluorine, we performed the molecular modeling studies of the cytidine analogue d-3'F-d4C and found a good correlation between calculated relative binding energies and activity/resistance data. Our model also shows interactions of the 3'-fluorine and the 2',3' double bond, which can be correlated to the observed biological data. Differences between fluorine substitution at the 3' and 2' positions may account for the higher cross-resistance with lamivudine observed in the 2'-fluorinated series.
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PMID:Synthesis, structure-activity relationships, and drug resistance of beta-d-3'-fluoro-2',3'-unsaturated nucleosides as anti-HIV Agents. 1518 36

The production of isotopically labeled RNA remains critical to current NMR structural studies. One approach to obtain simple NMR spectra is to label with a nucleus that is not naturally occurring in RNA. Fluorine-19 can serve as a sensitive site-specific probe upon incorporation into RNA. Here we report the efficient in vitro enzymatic synthesis of 2-fluoroadenosine-5'-triphosphate and its incorporation into the HIV-2 transactivation region (TAR) of RNA by DNA template-directed transcription using phage T7 RNA polymerase. We provide unequivocal evidence for this 19F-substituted base analogue capability to selectively interact with uracil, forming 2F-A-U base pairs in RNA. The introduction of a 2-fluoroadenyl substitution is relatively nonperturbing and provides us with uniquely positioned, sensitive NMR reporter groups to monitor structural changes in the local RNA environment.
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PMID:Enzymatic synthesis and 19F NMR studies of 2-fluoroadenine-substituted RNA. 1538 96


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