Metabolic pathways of N-methanocarbathymidine, a novel antiviral agent, in native and herpes simplex virus type 1 infected Vero cells

Zalah, Livnat; Huleihel, Mahmoud; Manor, Esther; Konson, Alexander; Ford, Harry; Márquez, Víctor E.; Johns, David G.; Agbaria, Riad

doi:10.1016/s0166-3542(02)00010-4

Cited by 41 publications

(45 citation statements)

References 29 publications

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“…Unlike acyclovir and GCV, which are selectively monophosphorylated in herpesvirus-infected cells because they are better substrates for virally encoded kinases than for cellular nucleoside kinases (17,19), N-MCT was found to be efficiently monophosphorylated in HSV-1-infected as well as in uninfected cells, indicating that the compound was a suitable substrate for cellular TK for monophosphorylation (64). However, the successive conversion of N-MCT-MP to N-MCT-DP and N-MCT-TP could only be detected in the HSV-1-infected cells, and the use of an HSV-1 TK inhibitor resulted in the accumulation of N-MCT-MP in the infected cells (64). HSV-1 TK is a multifunctional enzyme with diverse substrate specificity, known to exhibit TK and thymidylate kinase activities (10).…”

Section: Discussionmentioning

confidence: 99%

“…The unique aspects of intracellular phosphorylation of N-MCT were first discovered in HSV-1-infected cells (64). Unlike acyclovir and GCV, which are selectively monophosphorylated in herpesvirus-infected cells because they are better substrates for virally encoded kinases than for cellular nucleoside kinases (17,19), N-MCT was found to be efficiently monophosphorylated in HSV-1-infected as well as in uninfected cells, indicating that the compound was a suitable substrate for cellular TK for monophosphorylation (64).…”

Section: Discussionmentioning

confidence: 99%

“…The cell pellets were resuspended in 250 l of 60% methanol and heated at 95°C for 3 min, followed by a microcentrifugation at 12,000 ϫ g for 10 min at 4°C. The clarified supernatant fractions were evaporated under nitrogen, redissolved in 250 l of water, and subjected to high-pressure liquid chromatography (HPLC) separation of the phosphorylated metabolites as described in detail elsewhere (64). Fractions containing radiolabeled nucleotides were quantitated based on the known specific activity of the parent tritiated nucleoside (64).…”

Section: Methodsmentioning

confidence: 99%

“…The clarified supernatant fractions were evaporated under nitrogen, redissolved in 250 l of water, and subjected to high-pressure liquid chromatography (HPLC) separation of the phosphorylated metabolites as described in detail elsewhere (64). Fractions containing radiolabeled nucleotides were quantitated based on the known specific activity of the parent tritiated nucleoside (64). The phosphorylated metabolites of CDV were identified as CDV-phosphate, CDV-DP (active metabolite), and a phosphate ester adduct of CDV as previously described (28).…”

Section: Methodsmentioning

confidence: 99%

“…on May 12, 2018 by guest http://aac.asm.org/ coded TK/thymidylate kinase (10), as N-MCT-DP was thought to be readily phosphorylated to N-MCT-TP by cytosolic nucleoside diphosphate kinase (64). The discovery also suggested that N-MCT could be specifically activated (tri-phosphorylated) in cells infected with herpesviruses, which encoded TK/thymidylate kinases capable of recognizing N-MCT-MP as an optimal substrate.…”

Section: Vol 49 2005 Thymidine Analog N-mct Potent Inhibitor Of Ksmentioning

confidence: 99%

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Potent Antiviral Activity of North-Methanocarbathymidine against Kaposi's Sarcoma-Associated Herpesvirus

Zhu

Burnette

Dorjsuren

et al. 2005

Antimicrob Agents Chemother

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Kaposi's sarcoma-associated herpesvirus (KSHV) infection is a prerequisite for the development of Kaposi's sarcoma (KS).Kaposi's sarcoma (KS) is a multifocal malignant tumor of endothelial cell origin characterized by the proliferation of spindle-shaped cells with aberrant neovascularization and a large inflammatory cell infiltrate (14). KS usually manifests as pigmented nodular skin lesions, but can often spread to visceral organs in immunocompromised hosts, including AIDS patients (18, 34) and organ transplant recipients (15,46,54). This aggressive and disseminated form of KS was recognized as one of the first AIDS-defining conditions at the beginning of the human immunodeficiency virus (HIV) epidemic in the early 1980s (1, 29). Without effective therapy, visceral KS can be highly fatal unless the underlying causes of immune suppression are successfully treated (13, 21). Cytotoxic chemotherapeutic agents are commonly used in disseminated KS with response rates of up to 80% (22, 59). However, the majority of these agents are associated with serious side effects, and the tumor response to any chemotherapeutic regimen is only transient. There is no definitive cure for KS at the present time.KS-associated herpesvirus (KSHV, also called human herpesvirus 8) was first discovered in KS lesions obtained from patients with AIDS (9). It was subsequently found in all forms of KS and has strongly been implicated in the pathogenesis of KS (41). KSHV is a gamma-2 herpesvirus (genus Rhadinovirus) closely related to other oncogenic gammaherpesviruses, including herpesvirus saimiri (gamma-2), murine gammaherpesvirus (gamma-2), and Epstein-Barr virus (EBV) (gamma-1) (42). Since its discovery, KSHV has also been linked to a rare form of AIDSassociated effusion-based B-cell lymphoma, termed primary effusion lymphoma or body cavity-based lymphoma (BCBL) (8), and a subset of multicentric Castleman's disease (56).Although the exact etiologic mechanism of these neoplastic disorders is still unclear, KSHV infection is believed to play a critical role in the tumorigenesis and/or tumor progression. A number of studies have shown that higher levels of KSHV viral load in peripheral blood mononuclear cells and/or serum antibody titers against KSHV proteins correlated with increased risk of KS in HIV-infected (49, 60) and uninfected individuals (16,44). Higher KSHV viral load in peripheral blood has also been associated with progressive KS in HIV-infected individuals (6, 45). Moreover, several clinical studies, including one prospective study, have found that the risk of KS was significantly reduced in AIDS patients who received ganciclovir

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Vol 49 2005 Thymidine Analog N-mct Potent Inhibitor Of Ksmentioning

confidence: 99%

See 3 more Smart Citations

Potent Antiviral Activity of North-Methanocarbathymidine against Kaposi's Sarcoma-Associated Herpesvirus

Zhu

Burnette

Dorjsuren

et al. 2005

Antimicrob Agents Chemother

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Anti‐DNAVirus Agents

Holý

Clercq

2010

Burger's Medicinal Chemistry and Drug Discovery

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Anti‐DNA virus agents that are inhibitory to the replication of DNA viruses have been reviewed by Tim Middleton and Rockway in Burger's Medicinal Chemistry, 6th ed., volume 5. Here we will address the various agents effective against these different viruses. For each of the (classes of) compound(s), we will, where applicable, specifically focus on (i) the antiviral compounds that are clinically available; (ii) the antiviral compounds that are under (pre)clinical development; (iii) the mechanism of action of the compounds; (iv) their structure–activity relationship (SAR); (v) resistance that may have arisen; (vi) recent clinical data obtained with the compounds while under development. Previous reviews on antiviral agents have been dealing with “looking back in 2009 at the dawning of antiviral therapy now 50 years ago: an historical perspective,” highlighting the discovery of acyclovir [9‐(2‐hydroxyethoxymethyl)guanine] as a specific antiherpetic agent, “the design of drugs for HIV and HCV,” “HIV drug development: the next 25 years,” “interferons at age 50: past, current, and future impact on biomedicine,” “the way forward in HCV treatment‐finding the right path,” “antiviral treatment of chronic hepatitis B virus infections: the past, the present, and the future,” “antiviral agents active against influenza A viruses,” “the war against influenza: discovery and development of sialidase inhibitors,” “antivirals and antiviral strategies,” and “clinical potential of the acyclic nucleoside phosphonates cidofovir, adefovir, and tenofovir in treatment of DNA virus and retrovirus infections.”

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Total Syntheses of a Conformationally Locked North‐Type Methanocarba Puromycin Analogue and a Dinucleotide Derivative

Michel

Strazewski

2009

Chemistry A European J

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An original synthetic approach for the first synthesis of an enantiopure methanocarba puromycin (3'-alpha-aminoacylamino-3'-deoxyadenosine) analogue and its cytidine dinucleotide derivative is described. Each compound is conformationally locked in a North-type pucker and exhibits both a pseudoaxial hydroxy group and a pseudoequatorial aminoacyl group. The syntheses were accomplished from D-ribose in 18 and 19 steps, respectively, with key steps being a ring-closing metathesis, a Luche reduction, a Simmons-Smith cyclopropanation, a Mitsunobu coupling, a Mattocks bromoacetylation, a regioselective and a stereoselective nucleophilic substitution, a chemoselective phosphoramidite coupling and a Staudinger-Vilarrasa coupling. Both molecules are being tested for peptidyl transfer efficiency in ribosomes for comparison with the peptidyl transfer kinetics of natural puromycin and other natural and synthetic ribosomal A site substrates.

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Metabolic pathways of N-methanocarbathymidine, a novel antiviral agent, in native and herpes simplex virus type 1 infected Vero cells

Cited by 41 publications

References 29 publications

Potent Antiviral Activity of North-Methanocarbathymidine against Kaposi's Sarcoma-Associated Herpesvirus

Potent Antiviral Activity of North-Methanocarbathymidine against Kaposi's Sarcoma-Associated Herpesvirus

Anti‐DNAVirus Agents

Total Syntheses of a Conformationally Locked North‐Type Methanocarba Puromycin Analogue and a Dinucleotide Derivative

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