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

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

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

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

Antiviral Chemistry and Chemotherapy ◽

10.1177/2040206618813050 ◽

2018 ◽

Vol 26 ◽

pp. 204020661881305 ◽

Cited By ~ 1

Author(s):

Ondřej Baszczyňski ◽

Martin Maxmilian Kaiser ◽

Michal Česnek ◽

Petra Břehová ◽

Petr Jansa ◽

...

Keyword(s):

Purine Nucleotide ◽

Viral Dna ◽

Single Digit ◽

Varicella Zoster ◽

Dna And Rna ◽

Wide Range ◽

Acyclic Nucleoside Phosphonates ◽

Acyclic Nucleoside ◽

Human Herpesviruses ◽

Acyclic Nucleoside Phosphonate

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