Broad-spectrum anti-DNA virus and anti-retrovirus activity of phosphonylmethoxyalkylpurines and -pyrimidines

Clercq, Erik De

doi:10.1016/0006-2952(91)90276-b

Cited by 149 publications

(75 citation statements)

References 48 publications

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“…In addition to adenylyl cyclases, PMEApp inhibits viral re- verse transcriptases (13)(14)(15)(16). It is presumably this mechanism through which the oral prodrug derivative of PMEA (adefovir dipivoxil) effects the therapeutic and potent inhibition of retroviruses and hepatitis B virus (19,21,30), but it is less certain that this is the means by which this drug also enhances differentiation and exhibits anti-tumor activity (17)(18)(19).…”

Section: Discussionmentioning

confidence: 99%

“…Acyclic nucleoside phosphonates belong to a class of highly effective nucleotide analogs with broad spectrum antiviral activity (13)(14)(15)(16). Of these 9-(2-phosphonylmethoxyethyl)adenine (PMEA) has demonstrated antiviral activity against HIV and different types of DNA viruses (13)(14)(15)(16), differentiation-inducing activity (17,18), and anti-tumor activity (18,19).…”

mentioning

confidence: 99%

“…Of these 9-(2-phosphonylmethoxyethyl)adenine (PMEA) has demonstrated antiviral activity against HIV and different types of DNA viruses (13)(14)(15)(16), differentiation-inducing activity (17,18), and anti-tumor activity (18,19). A related acyclic adenine derivative, PMPA, also is active against HIV and several members of the herpesvirus family (15,20).…”

mentioning

confidence: 99%

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Inhibition of Adenylyl Cyclase by Acyclic Nucleoside Phosphonate Antiviral Agents

Shoshani

Laux

Philouze

et al. 1999

Journal of Biological Chemistry

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Acyclic derivatives of adenine, known as highly effective nucleotide analogs with broad spectrum antiviral activity, were evaluated for potential cross-reactivity with adenylyl cyclases, a family of membrane-bound enzymes that share putative topologies at their catalytic sites with oligonucleotide polymerases and reverse transcriptases. A series of derivatives of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) inhibited a preparation of adenylyl cyclase derived from rat brain with IC 50 values that ranged from 66 M (PMEA) to 175 nM for its diphosphate derivative (PMEApp) and mimics of it. PMEApp mimics included PMEAp(NH)p, PMEAp(CH 2 )p, PMEAp(CX 2 )p (X ‫؍‬ fluorine, chlorine, or bromine), PMEAp(CHX)pp, and PMEAp(C(OH)CH 3 pp. The data suggest that inhibition of adenylyl cyclases may contribute to the therapeutic action of some of these or similar compounds or constitute part of their side effects in therapeutic settings.Adenylyl cyclases are a family of membrane-bound enzymes central to one of the most important signal transduction systems and influence regulation of cell function in virtually all cells. The putative membrane topology of adenylyl cyclases conforms to a repeated sequence of a six-membrane spanning region followed by a cytosolic domain (1). The two cytosolic domains (C 1 and C 2 ) are homologous and contain regions that are highly conserved among adenylyl cyclase isozymes (1). The cleft formed by interaction of C 1 and C 2 contains the enzyme catalytic site (2, 3), the topology of which resembles aspects of the palm domain of DNA polymerases and human immunodeficiency virus (HIV) 1 reverse transcriptase (4 -7). Moreover, aspects of the catalytic mechanisms of adenylyl cyclases and enzymes involved in polymerization of oligonucleotides are similar as well. Each involves nucleoside triphosphate as substrate and divalent cation-dependent catalysis that includes attack involving the substrate 3Ј-OH group, to catalyze either chain elongation of a primer oligonucleotide or formation of the 3Ј:5Ј-cyclic phosphate, with pyrophosphate as a leaving group. Adenine nucleoside 3Ј-polyphosphates are among the most potent inhibitors of adenylyl cyclases (8 -11) and of these 2Ј-d-

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Inhibition of Adenylyl Cyclase by Acyclic Nucleoside Phosphonate Antiviral Agents

Shoshani

Laux

Philouze

et al. 1999

Journal of Biological Chemistry

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“…Acyclic nucleoside phosphonate 9-[2-(phosphonomethoxy)ethy]adenine (PMEA; adefovir) is a recognized antiviral agent possessing both antiherpesvirus and antiretroviral activities including anti-HIV effects [1][2][3][4] . The major disadvantage of this class of compounds under therapeutic usage is, however, rather poor intracellular delivery, intestinal permeation and limited oral bioavailability 5,6 .…”

Section: Introductionmentioning

confidence: 99%

Cytotoxicity of Pivoxil Esters of Antiviral Acyclic Nucleoside Phosphonates: Adefovir Dipivoxil Versus Adefovir

Zı́dek¹,

Kmoníčková²,

Holý³

2005

BIOMED PAP

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“…Acyclic nucleoside phosphonates [3] possess a phosphonate group attached to the acyclic nucleoside moiety through a stable P-C bond. In contrast to the phosphate group (which is attached through a P-O-C bond), a phosphonate group cannot be cleaved by cellular hydrolases.…”

mentioning

confidence: 99%

Acyclic Nucleoside Phosphonates: A New Dimension To The Chemotherapy Of Dna Virus And Retrovirus Infections

Clercq

1998

Journal of Medical Microbiology

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Most antiviral compounds that are currently used in the treatment of infection with herpes simplex virus (HSV), varicella-zoster virus (VZV) and cytomegalovirus (CMV) are acyclic nucleoside analogues: viz., acyclovir, penciclovir and ganciclovir [ 11. To increase their oral bioavailability, acyclovir and penciclovir have been converted to their oral prodrug forms, valaciclovir and famciclovir, respectively.

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Broad-spectrum anti-DNA virus and anti-retrovirus activity of phosphonylmethoxyalkylpurines and -pyrimidines

Cited by 149 publications

References 48 publications

Inhibition of Adenylyl Cyclase by Acyclic Nucleoside Phosphonate Antiviral Agents

Inhibition of Adenylyl Cyclase by Acyclic Nucleoside Phosphonate Antiviral Agents

Cytotoxicity of Pivoxil Esters of Antiviral Acyclic Nucleoside Phosphonates: Adefovir Dipivoxil Versus Adefovir

Acyclic Nucleoside Phosphonates: A New Dimension To The Chemotherapy Of Dna Virus And Retrovirus Infections

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