Epicatechin conjugated with fatty acid is a potent inhibitor of DNA polymerase and angiogenesis

Aurintricarboxylic acid (ATA) was found to be a very potent inhibitor of purified rabbit liver phosphofructokinase (PFK), giving 50% inhibition at 0.2 microM. The inhibition was in a manner consistent with interaction at the citrate-inhibitory site of the enzyme. The data suggest that inhibition of PFK by ATA was not due to denaturation of the enzyme or the irreversible binding of inhibitor, since the inhibition could be reversed by addition of allosteric activators of PFK, i.e. fructose 2,6-bisphosphate or AMP. Two other tricarboxylic acids, agaric acid and (-)-hydroxycitrate, were found to inhibit PFK. ATA at much higher concentrations (500 microM) was shown to inhibit fatty acid synthesis from endogenous glycogen in rat hepatocytes; however, protein synthesis was not altered.

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Catechin Conjugated with Fatty Acid Inhibits DNA Polymerase and Angiogenesis

DNA and Cell Biology ◽

10.1089/dna.2006.25.95 ◽

2006 ◽

Vol 25 (2) ◽

pp. 95-103 ◽

Cited By ~ 16

Author(s):

Kiminori Matsubara ◽

Akiko Saito ◽

Akira Tanaka ◽

Noriyuki Nakajima ◽

Reiko Akagi ◽

...

Keyword(s):

Fatty Acid ◽

Dna Polymerase

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Use of π-allyltricarbonyliron lactone complexes in the synthesis of taurospongin A: a potent inhibitor of DNA polymerase β and HIV reverse transcriptase

Organic & Biomolecular Chemistry ◽

10.1039/b301676p ◽

2003 ◽

Vol 1 (10) ◽

pp. 1664-1675 ◽

Cited By ~ 18

Author(s):

Christopher J. Hollowood ◽

Shigeo Yamanoi ◽

Steven V. Ley

Keyword(s):

Reverse Transcriptase ◽

Dna Polymerase ◽

Potent Inhibitor ◽

Hiv Reverse Transcriptase ◽

Dna Polymerase Β

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Acute and Delayed Toxicity Studies on the Antiherpesvirus Agents 5-Methoxymethyl-2′-Deoxycytidine and 5-Methoxymethyl-2′-Deoxyuridine

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029700800506 ◽

1997 ◽

Vol 8 (5) ◽

pp. 439-442

Author(s):

R Shi ◽

SV Gupta ◽

M Kukhanova ◽

SVP Kumar ◽

AL Stuart ◽

...

Keyword(s):

Mitochondrial Dna ◽

Dna Polymerase ◽

Doubling Time ◽

Prolonged Exposure ◽

Potent Inhibitor ◽

Control Drug ◽

Delayed Toxicity ◽

Simplex Virus ◽

Mitochondrial Dna Polymerase ◽

Dna Polymerase Γ

5-Methoxymethyl-2′-deoxycytidine (MMdCyd) and the corresponding deoxyuridine analogue, 5-methoxymethyl-2′-deoxyuridine (MMdUrd) are selective antiherpesvirus agents. MMdCyd (ED50 1.5 μM) is a more potent inhibitor of herpes simplex virus replication than MMdUrd (ED50 30 μM) when maintained in the deoxycytidine form (deamination prevented). The 5′-triphos-phates, MMdCTP and MMdUTP, were synthesized, and incorporation into DNA by mitochondrial DNA polymerase γ was investigated. MMdCTP and MMdUTP were incorporated into DNA in place of dCTP and dTTP, respectively. The effect of MMdCyd and MMdUrd on cell growth (acute toxicity) and prolonged exposure (delayed cytotoxicity) in CEM cells was investigated. The two analogues did not exhibit acute or delayed toxicity (2 weeks exposure) up to 1000 μM. In contrast, at a concentration as low as 0.125 μM of 2′,3′-dideoxycytidine (ddC; control drug), the doubling time of the cells increased after 10 days. At higher concentrations, a very marked increase in doubling time was observed from 6 days onward with ddC treatment. The data suggest that in uninfected cells neither MMdUrd nor MMdCyd are anabolized to the triphosphate form in significant amounts. As a result, little or no MMdCTP or MMdUTP builds up in the mitochondria and thus delayed toxicity is not observed.

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Inhibition of reverse transcriptases by seminalplasmin

Biochemical Journal ◽

10.1042/bj2090183 ◽

1983 ◽

Vol 209 (1) ◽

pp. 183-188 ◽

Cited By ~ 11

Author(s):

E S P Reddy ◽

M R Das ◽

E P Reddy ◽

P M Bhargava

Keyword(s):

Dna Polymerase ◽

Reproductive Tract ◽

Seminal Fluid ◽

Potent Inhibitor ◽

Female Reproductive Tract ◽

Dna Polymerase I ◽

Avian Myeloblastosis Virus ◽

Antibacterial Protein ◽

Reverse Transcriptases ◽

Polymerase I

Seminalplasmin, an antibacterial protein present in bovine seminal plasma, is shown to be a potent inhibitor of reverse transcriptases (RNA-dependent DNA nucleotidyltransferases). Seminalplasmin inhibits RNA-directed, hybrid-directed, and DNA-directed DNA-polymerizing activities of purified reverse transcriptase from avian myeloblastosis virus and from crude viral lysates of several retroviruses by binding to the enzyme, at least in the case of avian myeloblastosis virus. Seminalplasmin does not inhibit significantly DNA synthesis either by Escherichia coli DNA polymerase I, or a mammalian alpha-DNA polymerase. The presence of seminalplasmin in the seminal fluid could provide protection to the male and/or the female reproductive tract against retroviruses.

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Depside as potent inhibitor of prostaglandin biosynthesis: A new active site model for fatty acid cyclooxygenase

Prostaglandins ◽

10.1016/0090-6980(82)90174-5 ◽

1982 ◽

Vol 24 (1) ◽

pp. 21-34 ◽

Cited By ~ 28

Author(s):

Ushio Sankawa ◽

Masaaki Shibuya ◽

Yutaka Ebizuka ◽

Hiroshi Noguchi ◽

Yoichi Iitaka ◽

...

Keyword(s):

Fatty Acid ◽

Active Site ◽

Potent Inhibitor ◽

Prostaglandin Biosynthesis ◽

Site Model ◽

Active Site Model

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Potency and Stereoselectivity of Cyclopropavir Triphosphate Action on Human Cytomegalovirus DNA Polymerase

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00449-16 ◽

2016 ◽

Vol 60 (7) ◽

pp. 4176-4182 ◽

Cited By ~ 10

Author(s):

Han Chen ◽

Chengwei Li ◽

Jiri Zemlicka ◽

Brian G. Gentry ◽

Terry L. Bowlin ◽

...

Keyword(s):

Dna Synthesis ◽

Dna Polymerase ◽

Human Cytomegalovirus ◽

Potent Inhibitor ◽

Antiviral Drug ◽

Viral Polymerase ◽

Current Standard ◽

Hcmv Replication ◽

Additional Nucleotide ◽

Chain Terminators

ABSTRACTCyclopropavir (CPV) is a promising antiviral drug against human cytomegalovirus (HCMV). As with ganciclovir (GCV), the current standard for HCMV treatment, activation of CPV requires multiple steps of phosphorylation and is enantioselective. We hypothesized that the resulting CPV triphosphate (CPV-TP) would stereoselectively target HCMV DNA polymerase and terminate DNA synthesis. To test this hypothesis, we synthesized both enantiomers of CPV-TP [(+) and (−)] and investigated their action on HCMV polymerase. Both enantiomers inhibited HCMV polymerase competitively with dGTP, with (+)-CPV-TP exhibiting a more than 20-fold lower apparentKithan (−)-CPV-TP. Moreover, (+)-CPV-TP was a more potent inhibitor than GCV-TP. (+)-CPV-TP also exhibited substantially lower apparentKmand somewhat higher apparentkcatvalues than (−)-CPV-TP and GCV-TP for incorporation into DNA by the viral polymerase. As is the case for GCV-TP, both CPV-TP enantiomers behaved as nonobligate chain terminators, with the polymerase terminating DNA synthesis after incorporation of one additional nucleotide. These results elucidate how CPV-TP acts on HCMV DNA polymerase and help explain why CPV is more potent against HCMV replication than GCV.

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Lobucavir is phosphorylated in human cytomegalovirus-infected and -uninfected cells and inhibits the viral DNA polymerase.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.12.2680 ◽

1997 ◽

Vol 41 (12) ◽

pp. 2680-2685 ◽

Cited By ~ 33

Author(s):

D J Tenney ◽

G Yamanaka ◽

S M Voss ◽

C W Cianci ◽

A V Tuomari ◽

...

Keyword(s):

Protein Kinase ◽

Dna Synthesis ◽

Dna Polymerase ◽

Human Cytomegalovirus ◽

Potent Inhibitor ◽

Viral Dna ◽

Infected Cells ◽

Simplex Virus ◽

Hsv Thymidine Kinase

Lobucavir (LBV) is a deoxyguanine nucleoside analog with broad-spectrum antiviral activity. LBV was previously shown to inhibit herpes simplex virus (HSV) DNA polymerase after phosphorylation by the HSV thymidine kinase. Here we determined the mechanism of action of LBV against human cytomegalovirus (HCMV). LBV inhibited HCMV DNA synthesis to a degree comparable to that of ganciclovir (GCV), a drug known to target the viral DNA polymerase. The expression of late proteins and RNA, dependent on viral DNA synthesis, was also inhibited by LBV. Immediate-early and early HCMV gene expression was unaffected, suggesting that LBV acts temporally coincident with HCMV DNA synthesis and not through cytotoxicity. In vitro, the triphosphate of LBV was a potent inhibitor of HCMV DNA polymerase with a Ki of 5 nM. LBV was phosphorylated to its triphosphate form intracellularly in both infected and uninfected cells, with phosphorylated metabolite levels two- to threefold higher in infected cells. GCV-resistant HCMV isolates, with deficient GCV phosphorylation due to mutations in the UL97 protein kinase, remained sensitive to LBV. Overall, these results suggest that LBV-triphosphate halts HCMV DNA replication by inhibiting the viral DNA polymerase and that LBV phosphorylation can occur in the absence of viral factors including the UL97 protein kinase. Furthermore, LBV may be effective in the treatment of GCV-resistant HCMV.

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