scholarly journals Sulfoquinovosyldiacylglycerol, KM043, a New Potent Inhibitor of Eukaryotic DNA Polymerases and HIV-Reverse Transcriptase Type 1 from a Marine Red Alga, Gigartina tenella.

1998 ◽  
Vol 46 (4) ◽  
pp. 684-686 ◽  
Author(s):  
Keisuke OHTA ◽  
Yoshiyuki MIZUSHIMA ◽  
Noriko HIRATA ◽  
Masaharu TAKEMURA ◽  
Fumio SUGAWARA ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Potent Inhibitor ◽  
Dna Polymerases ◽  
Red Alga ◽  
Hiv Reverse Transcriptase ◽  
Eukaryotic Dna

scholarly journals Mode of inhibition of HIV reverse transcriptase by 2-hexaprenylhydroquinone, a novel general inhibitor of RNA-and DNA-directed DNA polymerases

1997 ◽  
Vol 324 (3) ◽  
pp. 721-727 ◽  
Author(s):  
Shoshana LOYA ◽  
Amira RUDI ◽  
Yoel KASHMAN ◽  
Amnon HIZI
Keyword(s):  
Reverse Transcriptase ◽  
Dna Polymerases ◽  
Competitive Inhibitor ◽  
Polymerization Process ◽  
Hiv Reverse Transcriptase ◽  
Allosteric Site ◽  
Leukaemia Virus ◽  
General Inhibitor ◽  
Hiv 1 ◽  
Rna And Dna

A natural compound from the Red Sea sponge Ircinia sp., 2-hexaprenylhydroquinone (HPH), has been shown to be a general inhibitor of retroviral reverse transcriptases (from HIV-1, HIV-2 and murine leukaemia virus) as well as of cellular DNA polymerases (Escherichia coli DNA polymerase I, and DNA polymerases α and β). The pattern of inhibition was found to be similar for all DNA polymerases tested. Thus the mode of inhibition was studied in detail for HIV-1 reverse transcriptase. HPH is a non-competitive inhibitor and binds the enzyme irreversibly with high affinity (Ki = 0.62 μM). The polar hydroxy groups have been shown to be of key importance. A methylated derivative, mHPH, which is devoid of these polar moieties, showed a significantly decreased capacity to inhibit all DNA polymerases tested. Like the natural product, mHPH binds the enzyme independently at an allosteric site, but with reduced affinity (Ki = 7.4 μM). We show that HPH does not interfere with the first step of the polymerization process, i.e. the physical formation of the reverse-transcriptase–DNA complex. Consequently, we suggest that the natural inhibitor interferes with the subsequent steps of the overall reaction. Since HPH seems not to affect the affinity of dNTP for the enzyme (the Km is unchanged under conditions where the HPH concentration is increased), we speculate that its inhibitory capacity is derived from its effect on the nucleotidyl-transfer catalytic reaction. We suggest that such a mechanism of inhibition is typical of an inhibitor whose mode of inhibition should be common to all RNA- and DNA-directed polymerases.

Robust Modeling and Scaffold Hopping: Case Study Based on HIV Reverse Transcriptase Inhibitors Type-1 Data

2016 ◽  
Vol 12 (6) ◽  
pp. 513-526
Author(s):  
Girinath G. Pillai ◽  
Laznier Mederos ◽  
Chandramukhi S. Panda ◽  
Amber Gronski ◽  
Peeter Burk ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Scaffold Hopping ◽  
Hiv Reverse Transcriptase ◽  
Reverse Transcriptase Inhibitors ◽  
Robust Modeling

scholarly journals Kinetic Interaction of the Diphosphates of 9-(2-phosphonylmethoxyethyl)adenine and Other anti-HIV Active Purine Congeners with HIV Reverse Transcriptase and Human DNA Polymerases α, β and γ

1995 ◽  
Vol 6 (4) ◽  
pp. 217-221 ◽  
Author(s):  
J. M. Cherrington ◽  
S. J. W. Allen ◽  
N. Bischofberger ◽  
M. S. Chen
Keyword(s):  
Reverse Transcriptase ◽  
Dna Polymerase ◽  
Dna Polymerases ◽  
Inhibitory Effects ◽  
Hiv Reverse Transcriptase ◽  
Dna Polymerase Β ◽  
Human Dna ◽  
Dna Template ◽  
Anti Hiv ◽  
Micromolar Range

The inhibitory effects of the diphosphates of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and its analogues on HIV reverse transcriptase and human DNA polymerases α, β, and γ have been studied. The analogues investigated are the diphosphates of 9-(2-phosphonylmethoxypropyl)adenine (PMPApp), 9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine (PMPDAPpp), and (2R,5R)-9-[2,5-dihydro-5-(phosphonyl methoxy)-2-furanyl]adenine (D4APpp). These four compounds are much more inhibitory to HIV reverse transcriptase when an RNA template rather than a DNA template is used. The Ki, values for the four compounds range from 11 to 22 nM with an RNA template. The Ki, values for ddCTP and AZTTP are 54 nM and 8 nM, respectively. PMEApp and its analogues show varying degrees of inhibition of the human DNA polymerases. The Ki, values for PMEApp, PMPApp and PMPDAPpp against DNA polymerase α are in the micromolar range, while D4APpp is a poor inhibitor of this enzyme with a Ki, value of 65.9 μM. The inhibition of DNA polymerase β by PMEApp, PMPApp and D4APpp is minimal, while PMPDAPpp shows higher inhibition of DNA polymerase β with a Ki, value of 9.71 μM. The Ki, values for PMEApp and D4APpp against DNA polymerase γ are submicromolar, while PMPApp and PMPDAPpp are much less inhibitory to this enzyme. For comparison, ddCTP was found to be a more potent inhibitor of DNA polymerases β and γ than the diphosphates of PMEA and its analogues.

scholarly journals Novel mutation (K70E) in human immunodeficiency virus type 1 reverse transcriptase confers decreased susceptibility to 9-[2-(phosphonomethoxy)ethyl]adenine in vitro.

1996 ◽  
Vol 40 (9) ◽  
pp. 2212-2216 ◽  
Author(s):  
J M Cherrington ◽  
A S Mulato ◽  
M D Fuller ◽  
M S Chen
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Novel Mutation ◽  
Fold Increase ◽  
Wild Type Virus ◽  
Wild Type ◽  
Hiv Reverse Transcriptase ◽  
Immunodeficiency Virus

9-[2-(phosphonomethoxy)ethyl]adenine (PMEA), an acyclic nucleoside phosphonate analog, is active against several retroviruses and herpesviruses and has shown anti-human immunodeficiency virus (HIV) activity in clinical trials. Serial passage of HIV type 1 (strain IIIb, in MT2 cells in increasing concentrations of PMEA resulted in viruses with > 12-fold increases in their 50% inhibitory concentrations of PMEA compared with that for strain IIIb. Sequence analyses of these PMEA-selected viruses demonstrated the presence of a novel lysine-to-glutamic acid mutation at amino acid 70 (K70E) in HIV reverse transcriptase. A recombinant virus carrying the K70E mutation was constructed and showed a 10-fold increase in its 50% inhibitory concentrations of PMEA and 2',3'-dideoxy-3'-thiacytidine but showed wild-type susceptibility levels to 2',3'-dideoxycytosine, 2',3'-dideoxyinosine,2',3'-didehydro-2'3'-dideoxythymidine, 3'-azido-3'-deoxythymidine, foscarnet, and two additional phosphonates, 9-[(R)-2-(phosphonomethoxy)propyl]adenine and 9-[2,5-dihydro-5-(phosphonomethoxy)-2-furanyl]adenine. Additionally, the K70E recombinant showed a minor reduction in growth kinetics compared with those of the wild-type virus in vitro.

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