Xanthine-based acyclic nucleoside phosphonates with potent antiviral activity against varicella-zoster virus and human cytomegalovirus

While noncanonic xanthine nucleotides XMP/dXMP play an important role in balancing and maintaining intracellular purine nucleotide pool as well as in potential mutagenesis, surprisingly, acyclic nucleoside phosphonates bearing a xanthine nucleobase have not been studied so far for their antiviral properties. Herein, we report the synthesis of a series of xanthine-based acyclic nucleoside phosphonates and evaluation of their activity against a wide range of DNA and RNA viruses. Two acyclic nucleoside phosphonates within the series, namely 9-[2-(phosphonomethoxy)ethyl]xanthine (PMEX) and 9-[3-hydroxy-2-(phosphonomethoxy)propyl]xanthine (HPMPX), were shown to possess activity against several human herpesviruses. The most potent compound was PMEX, a xanthine analogue of adefovir (PMEA). PMEX exhibited a single digit µM activity against VZV (EC50 = 2.6 µM, TK+ Oka strain) and HCMV (EC50 = 8.5 µM, Davis strain), while its hexadecyloxypropyl monoester derivative was active against HSV-1 and HSV-2 (EC50 values between 1.8 and 4.0 µM). In contrast to acyclovir, PMEX remained active against the TK– VZV 07–1 strain with EC50 = 4.58 µM. PMEX was suggested to act as an inhibitor of viral DNA polymerase and represents the first reported xanthine-based acyclic nucleoside phosphonate with potent antiviral properties.

Download Full-text

Interaction of Phosphates of the Acyclic Nucleoside Phosphonates with Nucleoside Diphosphate Kinase from Yeast and Bovine Liver

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc20060035 ◽

2006 ◽

Vol 71 (1) ◽

pp. 35-43 ◽

Cited By ~ 6

Author(s):

Květoslava Horská ◽

Ivan Votruba ◽

Antonín Holý

Keyword(s):

Nucleoside Diphosphate Kinase ◽

Bovine Liver ◽

Kinetic Constants ◽

Aliphatic Chain ◽

Ndp Kinase ◽

Hydroxymethyl Group ◽

Acyclic Nucleoside Phosphonates ◽

Acyclic Nucleoside ◽

Acyclic Nucleoside Phosphonate

The ability of monophosphates of selected acyclic nucleoside phosphonates to serve as substrates for the title NDP kinases was studied. Comparison of the kinetic constants (KM, Vmax, kcat and kcat/KM) estimates indicates that the yeast enzyme catalyzes the phosphorylation of purine and pyrimidine acyclic nucleoside phosphate phosphonates of the 9-[2-(phosphonomethoxy)ethyl] and/or 9-[2-(phosphonomethoxy)propyl] series more efficiently than bovine liver NDP kinase. Yeast enzyme preferentially phosphorylates phosphates of the (phosphono- methoxyalkyl)guanines rather than their adenine counterparts; both enzymes phosphorylate R-enantiomers of the 9-[2-(phosphonomethoxy)propyl] series more efficiently than the corresponding S-enantiomers. Substitution of the aliphatic chain at the position 3 with hydroxymethyl group considerably increases the substrate activity of phosphate of acyclic nucleoside phosphonate. The resulting substrate activity (kcat/KM ratio) of all acyclic nucleoside phosphonate phosphates studied is three to five orders of magnitude lower than that for natural NDPs.

Download Full-text

Human N6-Methyl-AMP/DAMP Aminohydrolase (Abacavir 5'-Monophosphate Deaminase) is Capable of Metabolizing N6-Substituted Purine Acyclic Nucleoside Phosphonates

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc20080275 ◽

2008 ◽

Vol 73 (2) ◽

pp. 275-291 ◽

Cited By ~ 13

Author(s):

Markéta Schinkmanová ◽

Ivan Votruba ◽

Riri Shibata ◽

Bin Han ◽

Xiaohong Liu ◽

...

Keyword(s):

Biologically Active ◽

Side Chain ◽

Moderate Increase ◽

Intracellular Metabolite ◽

Nucleotide Analogs ◽

Substrate Specificities ◽

Highly Sensitive ◽

Acyclic Nucleoside Phosphonates ◽

Acyclic Nucleoside ◽

Acyclic Nucleoside Phosphonate

Recombinant human abacavir monophosphate deaminase (hABC-MP deaminase) was compared with the recently described ratN6-methyl-AMP (meAMP) aminohydrolase. hABC-MP deaminase, a 42 kDa polypeptide, exists predominantly as a monomer under non-denaturing conditions. Similar to the rat enzyme, hABC-MP deaminase efficiently catalyzes the hydrolytic deamination of natural substrates meAMP (5),N6,N6-dimethyl-AMP (13) and medAMP (6). Acyclic nucleoside phosphonate (ANP)N6-cyclopropyl-2,6-diamino-9-[2-(phosphonomethoxy)ethyl]purine (cPrPMEDAP) (1), an intermediate intracellular metabolite of antileukemic agent GS-9219, was effectively converted to the corresponding active guanine analog by hABC-MP deaminase. In addition to cPrPMEDAP (1), a number of other biologically activeN6-substituted purine ANPs are alternative substrates for hABC-MP deaminase. The efficiency of their deamination depends on the character ofN6-substitution in the adenine and/or 2,6-diaminopurine ring. ANPs withN6-cyclic substituents are deaminated more readily than corresponding compounds with aliphatic substituents of the same length. The deamination of ANPs is also influenced by modifications at the phosphonoalkyl side chain. Among 9-[2-(phosphonomethoxy)propyl] ANPs, (S)-enantiomers are preferred to (R)-enantiomers. Alternatively, the presence of extended 9-[2-(phosphonoethoxy)ethyl] moiety leads to a moderate increase in the reaction velocity compared to cPrPMEDAP (1). Comparison of hABC-MP deaminase and the rat meAMP aminohydrolase across a broad spectrum ofN6-substituted substrates revealed a strong correlation of their substrate specificities. Similar to the rat meAMP aminohydrolase, hABC-MP deaminase was highly sensitive to deoxycoformycin monophosphate, but not to the guanine product of cPrPMEDAP (1) deamination. Together, these data demonstrate that hABC-MP deaminase is human meAMP aminohydrolase involved in the intracellular activation of biologically activeN6-substituted nucleotide analogs.

Download Full-text

120 Dipyridamole potentiates the activity of acyclic nucleoside phosphonates against varicella-zoster virus (VZV), herpes simplex virus (HSV) and human cytomegalovirus (HCMV) in vitro

Antiviral Research ◽

10.1016/0166-3542(93)90498-8 ◽

1993 ◽

Vol 20 ◽

pp. 109

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Varicella Zoster Virus ◽

Human Cytomegalovirus ◽

Varicella Zoster ◽

Acyclic Nucleoside Phosphonates ◽

Acyclic Nucleoside ◽

Simplex Virus

Download Full-text

HPMPC (cidofovir), PMEA (adefovir) and Related Acyclic Nucleoside Phosphonate Analogues: A Review of their Pharmacology and Clinical Potential in the Treatment of Viral Infections

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029700800101 ◽

1997 ◽

Vol 8 (1) ◽

pp. 1-23 ◽

Cited By ~ 174

Author(s):

L Naesens ◽

R Snoeck ◽

G Andrei ◽

J Balzarini ◽

J Neyts ◽

...

Keyword(s):

Broad Spectrum ◽

Viral Infections ◽

Specific Interaction ◽

Hiv Infections ◽

Concomitant Administration ◽

Varicella Zoster ◽

Acyclic Nucleoside ◽

Acyclic Nucleoside Phosphonate

The acyclic nucleoside phosphonate (ANP) analogues are broad-spectrum antiviral agents, with potent and selective antiviral activity in vitro and in vivo. The prototype compounds are: ( S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC, cidofovir), which is active against a wide variety of DNA viruses; 9-(2-phosphonylmethoxyethyl)adenine (PMEA, adefovir), which is active against retro-, herpes- and hepadnaviruses, and ( R)-9-(2-phosphonylmethoxypropyl) adenine (PMPA), which is active against retro- and hepadnaviruses. The antiviral action of the ANP analogues is based on a specific interaction of the active diphosphorylated metabolite with the viral DNA polymerase. The long intracellular half-life of the active metabolite accounts for the optimal efficacy in infrequent dosing schedules. The potential of HPMPC as a broad-spectrum anti-DNA virus agent, as originally observed in vitro and in vivo, has been confirmed in clinical trials. HPMPC has recently been commercially released in the USA for the treatment of cytomegalovirus retinitis in AIDS patients. In addition, topical systemic HPMPC is being (or will be) explored for use against other herpesviruses (i.e. herpes simplex virus, Epstein-Barr virus, or varicella-zoster virus), by adenoviruses, or by human papilloma- or polyomaviruses. Intravenous HPMPC is associated with dose-dependent nephrotoxicity, that should be counteracted by prehydration and concomitant administration of probenecid, and by the application of an infrequent dosing schedule. The oral prodrug of PMEA, bis(pivaloyloxymethyl)-PMEA, is currently being evaluated in patients infected with human immunodeficiency virus (HIV) or hepatitis B virus. Finally, preclinical data on the efficacy of PMPA in animal retrovirus models point to its potential usefulness against HIV infections, when given either prophylactically or therapeutically in the treatment of established HIV infections.

Download Full-text

Novel Acyclic Nucleoside Phosphonate Analogues with Potent Anti-Hepatitis B Virus Activities

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.3.1177-1180.2005 ◽

2005 ◽

Vol 49 (3) ◽

pp. 1177-1180 ◽

Cited By ~ 34

Author(s):

C. Ying ◽

A. Holý ◽

D. Hocková ◽

Z. Havlas ◽

E. De Clercq ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Amino Group ◽

Wild Type ◽

Pyrimidine Base ◽

B Virus ◽

Acyclic Nucleoside Phosphonates ◽

Acyclic Nucleoside ◽

Acyclic Nucleoside Phosphonate

ABSTRACT Novel acyclic nucleoside phosphonates with a pyrimidine base preferentially containing an amino group at C-2 and C-4 and a 2-(phosphonomethoxy)ethoxy or (R)-2-(phosphonomethoxy)propoxy group at C-6 selectively inhibit the replication of wild-type and lamivudine-resistant hepatitis B viruses. The activity of the most potent compounds was comparable to that of adefovir.

Download Full-text

Palladium-catalyzed allylic amination: a powerful tool for the enantioselective synthesis of acyclic nucleoside phosphonates

Organic & Biomolecular Chemistry ◽

10.1039/c7ob01478c ◽

2017 ◽

Vol 15 (34) ◽

pp. 7227-7234 ◽

Cited By ~ 4

Author(s):

Mariam Azzouz ◽

Sébastien Soriano ◽

Margarita Escudero-Casao ◽

M. Isabel Matheu ◽

Sergio Castillón ◽

...

Keyword(s):

Enantioselective Synthesis ◽

High Yield ◽

Allylic Substitution ◽

Allylic Amination ◽

Palladium Catalyzed ◽

Acyclic Nucleoside Phosphonates ◽

Acyclic Nucleoside ◽

Acyclic Nucleoside Phosphonate

Acyclic nucleoside phosphonate were prepared in high yield and up to 92% ee using an enantioselective palladium-catalyzed allylic substitution.

Download Full-text

Dipyridamole Potentiates the Activity of Various Acyclic Nucleoside Phosphonates against Varicella-Zoster Virus, Herpes Simplex Virus and Human Cytomegalovirus

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029400500505 ◽

1994 ◽

Vol 5 (5) ◽

pp. 312-321 ◽

Cited By ~ 7

Author(s):

R. Snoeck ◽

G. Andrei ◽

J. Balzarini ◽

D. Reymen ◽

E. De Clercq

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Varicella Zoster Virus ◽

Human Cytomegalovirus ◽

Varicella Zoster ◽

Antiviral Effects ◽

Acyclic Nucleoside Phosphonates ◽

Acyclic Nucleoside ◽

Simplex Virus ◽

Derivatives Of

Dypiridamole (DPM) is widely used in the treatment of cardiovascular diseases as a coronary vasodilator and inhibitor of platelet aggregation. Phosphonylmethoxyethyl (PME) and 3-hydroxy-2-phosphonylmethoxypropyl (HPMP) derivatives of purines and pyrimidines are potent and selective inhibitors of varicella-zoster virus (VZV), herpes simplex virus (HSV) and human cytomegalovirus (HCMV). We have found that DPM markedly potentiates the antiviral effects of the PME derivatives of adenine (PMEA) and 2,6-diaminopurine (PMEDAP), and of the HPMP derivatives of adenine (HPMPA), 3-deazaadenine (HPMPc3A) and cyclic HPMPA (cHPMPA). This was reflected by a significant decrease in the 50% inhibitory concentration of the acyclic nucleoside phosphonates for VZV-, HSV- and HCMV-induced cytopathic effect or plaque formation. DPM did not enhance the activity of vidarabine, acyclovir or ganciclovir. These results were confirmed by virus yield assays (for HSV and HCMV) and flow cytometry (for VZV).

Download Full-text

DIAGNOSTIC VALUE OF SPECIFIC ANTIBODY SYNTHESIS IN BRAIN OF PATIENTS WITH NEUROINFECTIONS

Wiadomości Lekarskie ◽

10.36740/wlek201908103 ◽

2019 ◽

Vol 72 (8) ◽

pp. 1437-1441

Author(s):

Pavel Dyachenko ◽

Igor Filchakov ◽

Anatoly Dyachenko ◽

Victoria Kurhanskaya

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Clinical Manifestations ◽

Diagnostic Value ◽

Diagnostic Challenge ◽

Specific Antibodies ◽

Intrathecal Synthesis ◽

Varicella Zoster ◽

Mrz Reaction ◽

Wide Range

Introduction: Viral encephalitis accounts for 40-70% of all cases worldwide, central nervous system infections pose a diagnostic challenge because clinical manifestations are not typically pathognomonic for specific pathogens, and a wide range of agents can be causative. The aim: To assess the diagnostic value of intrathecal synthesis of specific antibodies in patients with inflammatory lesions of the central nervous system. Materials and methods: Within the framework of the study, two groups of 90 people in each were formed from the patients with neuroinfections admitted to our Center. Intrathecal synthesis (ITS) of total (unspecific) IgG in members of one of group (group of compare) was determined. Brain synthesis of specific antibodies (Ab) to some neurotropic pathogens (herpes simplex virus 1/2, cytomegalovirus, Epstein-Barr virus, varicella zoster virus, rubella virus, Borrelies) was studied in the second group of patients (group of interest). There were no statistically significant differences between groups by gender and age. Encephalitis and encephalomyelitis prevailed among patients of both groups Results: ITS of total IgG was established in 30 (33.3 ± 6.1 %) patients of the first group with IgG index more than 0.6 indicating on inflammatory process in CNS and no marked changes of CSF. ITS of specific Ab was determined in 23 of 90 (25.6 ± 4.6 %) patients included into group of interest. In more than half of cases Ab to several infectious agents were detected simultaneously. ITS of various specificity, in particular, to measles and rubella viruses, and VZV, known as MRZ-reaction, is characteristic of some autoimmune lesions of CNS, multiple sclerosis first of all. In fact, further research of 5 patients with MRZ-reaction confirmed their autoimmune failure of CNS. Detection of ITS in the CSF samples didn’t depend on concentration of specific Ab in serum and CSF and wasn’t followed by HEB dysfunctions which were observed with the same frequency in patients with or without ITS (13.0 % and 13.6 % respectively). Conclusion: Specific Ab synthesis to several neurotropic pathogens in the CSF of significant part of examined patients was established. Thus, diagnostic value of ITS of specific immunoglobulins seems to be limited to cases in which autoimmune damage of the CNS is suspected.

Download Full-text