1-(2,3-Dideoxy-.beta.-D-glycero-pent-2-enofuranosyl)thymine. A highly potent and selective anti-HIV agent

Mansuri, Muzammil M.; Starrett, John E.; Ghazzouli, Ismail; Hitchcock, Michael; Sterzycki, Roman Z.; Brankovan, V.; Lin, Tsung‐I; August, Elias; Prusoff, William H.

doi:10.1021/jm00122a029

Cited by 207 publications

(48 citation statements)

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“…We believe that the FIV systems will enable coordination of in vivo and in vitro experiments and that these studies can provide information that will be important in the design of chemotherapeutic strategies for AIDS in humans. On the basis of the results of this investigation and the proven anti-HIV activities of 3'-azido-3'-deoxythymidine (4, 10) and 2',3'-dideoxy-2',3'-didehydrothymidine (1,6,8,9), these two compounds look particularly attractive for further studies with the FIV model. We thank Niels C. Pedersen and Y.-C. Cheng for much helpful discussion.…”

mentioning

confidence: 96%

Direct comparisons of inhibitor sensitivities of reverse transcriptases from feline and human immunodeficiency viruses

North

Cronn

Remington

et al. 1990

Antimicrob Agents Chemother

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The sensitivities of reverse transcriptases (RTs) from feline immunodeficiency virus (FIV) and human immunodeficiency virus type 1 (HIV) were directly compared. The two enzymes had similar sensitivities to three analogs of dTTP, namely, 3'-azido-3'-deoxythymidine 5'-triphosphate, 2',3'-dideoxythymidine 5'-triphosphate, and 2',3'-dideoxy-2',3'-didehydrothymidine 5'-triphosphate. Each of these analogs demonstrated competitive inhibition of both enzymes. Ki values for inhibition of FIV RT by these three inhibitors were 3.3, 6.7, and 1.8 nM, respectively; Ki values for inhibition of the HIV enzyme were 6.5, 5.9, and 8.3 nM, respectively. Ratios of the Ki for the inhibitor to the Km for the substrate were also determined for each inhibitor, and no differences between the two enzymes greater than threefold were observed. Inhibition constants for 3'-amino-3'-deoxythymidine 5'-triphosphate and 3'-fluoro-3'-deoxythymidine 5'-triphosphate were determined for FIV RT, and these were similar to published values for HIV RT. The activities of three dideoxynucleoside 5'-triphosphates against FIV RT were determined; ddGTP was slightly more potent than ddTTP, whereas both were much more effective than ddCTP. The activity of a noncompetitive inhibitor, phosphonoformate, was also examined with the FIV enzyme; it was much more active with poly(rA)-oligo(dT) as the template-primer than with poly(rC)-oligo(dG) or poly(rI)-oligo(dC).

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mentioning

confidence: 96%

Direct comparisons of inhibitor sensitivities of reverse transcriptases from feline and human immunodeficiency viruses

North

Cronn

Remington

et al. 1990

Antimicrob Agents Chemother

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“…37,38,39,40,41,42 Many purine nucleoside and their derivatives have shown to have prominent anti-viral activity against some of the most deadly viruses found like human immune-deficiency virus (HIV), herpes simplex virus (HSV), vaccinia virus, respiratory syncytial virus, hepatitis B virus (HBV), human cytomegalovirus (HCMV) and varicella zoster virus (VZV). [43][44][45][46][47][48] Abacavir (DB01048), a guanosine analogue is known for its activity against retrovirus (HIV, Moloney sarcoma virus) and herpes simplex virus (HSV) activity in cell culture. 38 In a study conducted in University of Alabama at Birmingham, USA, the structural similarities between M1 matrix protein of Influenza A virus (having RNA nucleocapsid-binding activities) and HIV matrix and capsid proteins was ascertained, establishing an evolutionary link between retroviruses and negative strand Table 2: Absorption, distribution, metabolism, and excretion (ADME) properties of screened hit molecules.…”

Section: Discussionmentioning

confidence: 99%

Energy Based Pharmacophore Modelling and Docking Studies for Determining Potent Inhibitor Against M2 Proton Channel of Influenza Virus

Kanagavelu¹,

Sunny²,

Balasundaram³

et al. 2018

IJPER

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M2 protein, a crucial glycoprotein present on the viral envelope of Influenza A virus plays an important role in the replication and budding of influenza A virus in the host organism. Due to its primal role in the life cycle of influenza A virus, it is targeted by many potent drugs like amantadine and rimantadine. The emergence of M2 protein mutants in the recent years has rendered these drugs ineffective. Keeping this in our minds, an investigation was performed to determine potent inhibitors of M2 protein using computational strategies like e-pharmacophore based virtual screening and molecular docking. A three dimensional pharmacophore model was generated based on the chemical features using PHASE module of Schrödinger Suite. Subsequently, molecules with same pharmacophoric features were screened from a total of 8621 molecules available in the DrugBank database using the generated pharmacophore hypothesis. This was followed by molecular docking of the screened molecules using three methodologies namely HTVS, SP and XP. Ligand filtration was also done to obtain an efficient collection of hit molecules by analysing pharmacokinetic properties by using Qikprop module. Consequently, our study ascertained nine molecules namely, DB00374, DB00770, DB05015, DB08868, DB00631, DB00983, DB01262, DB00837 and DB01048 which were found to possess anti-viral properties. It is also worth mentioning that antiviral activity of these compounds has been previously reported in recent literature.

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“…Dideoxythymidinine, also known as D4T, has good activity against HIV but is phosphorylated differently from zidovudine and has less bone marrow toxicity (205,284). Azidouridine is slightly less active against HIV than zidovudine, but is also less toxic to bone marrow (67,531), and it (Fig.…”

Section: Zidovudinementioning

confidence: 99%

Antiviral therapy: current concepts and practices

Bean

1992

Clin Microbiol Rev

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Drugs capable of inhibiting viruses in vitro were described in the 1950s, but real progress was not made until the 1970s, when agents capable of inhibiting virus-specific enzymes were first identified. The last decade has seen rapid progress in both our understanding of antiviral therapy and the number of antiviral agents on the market. Amantadine and ribavirin are available for treatment of viral respiratory infections. Vidarabine, acyclovir, ganciclovir, and foscarnet are used for systemic treatment of herpesvirus infections, while ophthalmic preparations of idoxuridine, trifluorothymidine, and vidarabine are available for herpes keratitis. For treatment of human immunodeficiency virus infections, zidovudine and didanosine are used. Immunomodulators, such as interferons and colony-stimulating factors, and immunoglobulins are being used increasingly for viral illnesses. While resistance to antiviral drugs has been seen, especially among AIDS patients, it has not become widespread and is being intensely studied. Increasingly, combinations of agents are being used: to achieve synergistic inhibition of viruses, to delay or prevent resistance, and to decrease dosages of toxic drugs. New approaches, such as liposomes carrying antiviral drugs and computer-aided drug design, are exciting and promising prospects for the future.

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1-(2,3-Dideoxy-.beta.-D-glycero-pent-2-enofuranosyl)thymine. A highly potent and selective anti-HIV agent

Cited by 207 publications

References 2 publications

Direct comparisons of inhibitor sensitivities of reverse transcriptases from feline and human immunodeficiency viruses

Direct comparisons of inhibitor sensitivities of reverse transcriptases from feline and human immunodeficiency viruses

Energy Based Pharmacophore Modelling and Docking Studies for Determining Potent Inhibitor Against M2 Proton Channel of Influenza Virus

Antiviral therapy: current concepts and practices

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