scholarly journals Acaconin, a chitinase-like antifungal protein with cytotoxic and anti-HIV-1 reverse transcriptase activities from Acacia confusa seeds.

2010 ◽  
Vol 57 (3) ◽  
Author(s):  
Sze Kwan Lam ◽  
Tzi Bun Ng
Keyword(s):  
Antifungal Activity ◽  
Reverse Transcriptase ◽  
Rhizoctonia Solani ◽  
Fungal Growth ◽  
Chitinase Activity ◽  
Antifungal Protein ◽  
Hiv Reverse Transcriptase ◽  
Acacia Confusa ◽  
Congo Red Staining ◽  
Hiv 1

From the seeds of Acacia confusa, a chitinase-like antifungal protein designated as acaconin that demonstrated antifungal activity toward Rhizoctonia solani with an IC₅₀ of 30±4 µM was isolated. Acaconin demonstrated an N-terminal sequence with pronounced similarity to chitinases and a molecular mass of 32 kDa. It was isolated by chromatography on Q-Sepharose, SP-Sepharose and Superdex 75 and was not bound by either ion exchanger. Acaconin was devoid of chitinase activity. The antifungal activity against Rhizoctonia solani was completely preserved from pH 4 to 10 and from 0°C to 70°C. Congo Red staining at the tips of R. solani hyphae indicated inhibition of fungal growth. However, there was no antifungal activity toward Mycosphaerella arachidicola, Fusarium oxysporum, Helminthosporium maydis, and Valsa mali. Acaconin inhibited proliferation of breast cancer MCF-7 cells with an IC₅₀ of 128±9 µM but did not affect hepatoma HepG2 cells. Its IC₅₀ value toward HIV-1 reverse transcriptase was 10±2.3 µM. The unique features of acaconin include relatively high stability when exposed to changes in ambient pH and temperature, specific antifungal and antitumor actions, potent HIV-reverse transcriptase inhibitory activity, and lack of binding by strongly cationic and anionic exchangers.

scholarly journals Fullerene Derivatives of Nucleoside HIV Reverse Transcriptase Inhibitors—In Silico Activity Prediction

2018 ◽  
Vol 19 (10) ◽  
pp. 3231 ◽  
Author(s):  
Aleksandra Dąbrowska ◽  
Tomasz Pieńko ◽  
Przemysław Taciak ◽  
Katarzyna Wiktorska ◽  
Zdzisław Chilmonczyk ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Hiv Reverse Transcriptase ◽  
Reverse Transcriptase Inhibitors ◽  
Activity Prediction ◽  
Hiv Therapy ◽  
C20 Fullerene ◽  
Derivatives Of ◽  
Anti Hiv ◽  
Similar Affinity ◽  
Hiv 1

Here we present new derivatives of nucleoside reverse transcriptase inhibitors with a C20 fullerene. The computational chemistry methods used in this study evaluate affinity of designed compounds towards the HIV-1 reverse transcriptase (RT) binding site and select the most active ones. The best of the designed compounds have superior or similar affinity to RT active site in comparison to most active test compounds, including drugs used in anti-HIV therapy.

scholarly journals Effects of the W153L Substitution in HIV Reverse Transcriptase on Viral Replication and Drug Resistance to Multiple Categories of Reverse Transcriptase Inhibitors

2014 ◽  
Vol 58 (8) ◽  
pp. 4515-4526 ◽  
Author(s):  
Hong-Tao Xu ◽  
Susan P. Colby-Germinario ◽  
Maureen Oliveira ◽  
Daniel Rajotte ◽  
Richard Bethell ◽  
...  
Keyword(s):  
Viral Replication ◽  
Reverse Transcriptase ◽  
Rnase H ◽  
Hiv Reverse Transcriptase ◽  
Compound A ◽  
Enzymatic Function ◽  
Biochemical Assays ◽  
Rt Inhibitors ◽  
The Impact ◽  
Hiv 1

ABSTRACTA W153L substitution in HIV-1 reverse transcriptase (RT) was recently identified by selection with a novel nucleotide-competing RT inhibitor (NcRTI) termed compound A that is a member of the benzo[4,5]furo[3,2,d]pyrimidin-2-one NcRTI family of drugs. To investigate the impact of W153L, alone or in combination with the clinically relevant RT resistance substitutions K65R (change of Lys to Arg at position 65), M184I, K101E, K103N, E138K, and Y181C, on HIV-1 phenotypic susceptibility, viral replication, and RT enzymatic function, we generated recombinant RT enzymes and viruses containing each of these substitutions or various combinations of them. We found that W153L-containing viruses were impaired in viral replicative capacity and were hypersusceptible to tenofovir (TFV) while retaining susceptibility to most nonnucleoside RT inhibitors. The nucleoside 3TC retained potency against W153L-containing viruses but not when the M184I substitution was also present. W153L was also able to reverse the effects of the K65R substitution on resistance to TFV, and K65R conferred hypersusceptibility to compound A. Biochemical assays demonstrated that W153L alone or in combination with K65R, M184I, K101E, K103N, E138K, and Y181C impaired enzyme processivity and polymerization efficiency but did not diminish RNase H activity, providing mechanistic insights into the low replicative fitness associated with these substitutions. We show that the mechanism of the TFV hypersusceptibility conferred by W153L is mainly due to increased efficiency of TFV-diphosphate incorporation. These results demonstrate that compound A and/or derivatives thereof have the potential to be important antiretroviral agents that may be combined with tenofovir to achieve synergistic results.

Tricholoma matsutake fruit bodies secrete hydrogen peroxide as a potent inhibitor of fungal growth

2015 ◽  
Vol 61 (6) ◽  
pp. 447-450 ◽  
Author(s):  
Yoshimitsu Takakura
Keyword(s):  
Hydrogen Peroxide ◽  
Antimicrobial Activity ◽  
Antifungal Activity ◽  
Rhizoctonia Solani ◽  
Microbial Communities ◽  
Potent Inhibitor ◽  
Fungal Growth ◽  
Ectomycorrhizal Fungus ◽  
Tricholoma Matsutake ◽  
Pyranose Oxidase

Tricholoma matsutake is an ectomycorrhizal fungus that dominates the microbial communities in the soil of pine and spruce forests. The mycorrhizas of this fungus have antimicrobial activity, although factors responsible for the antimicrobial activity have not been fully elucidated. The present study shows that fruit bodies of T. matsutake secreted hydrogen peroxide (H2O2), which was produced by pyranose oxidase, and that the H2O2 thus secreted strongly inhibited the growth of mycelia of the phytopathological fungus Rhizoctonia solani. These findings suggest that fruit bodies of T. matsutake have antifungal activity and that the pyranose oxidase plays an important role in the antifungal activity.

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.

PASS-based approach to predict HIV-1 reverse transcriptase resistance

2017 ◽  
Vol 15 (02) ◽  
pp. 1650040 ◽  
Author(s):  
Olga Tarasova ◽  
Dmitry Filimonov ◽  
Vladimir Poroikov
Keyword(s):  
Amino Acid ◽  
Reverse Transcriptase ◽  
Open Data ◽  
Amino Acid Substitutions ◽  
Hiv Reverse Transcriptase ◽  
Hiv Rt ◽  
Hiv Drugs ◽  
Rt Inhibitors ◽  
Anti Hiv ◽  
Hiv 1

HIV reverse transcriptase (RT) inhibitors targeting the early stages of virus–host interactions are of great interest to scientists. Acquired HIV RT resistance happens due to mutations in a particular region of the pol gene encoding the HIV RT amino acid sequence. We propose an application of the previously developed PASS algorithm for prediction of amino acid substitutions potentially involved in the resistance of HIV-1 based on open data. In our work, we used more than 3200 HIV-1 RT variants from the publicly available Stanford HIV RT and protease sequence database already tested for 10 anti-HIV drugs including both nucleoside and non-nucleoside RT inhibitors. We used a particular amino acid residue and its position to describe primary structure-resistance relationships. The average balanced accuracy of the prediction obtained in 20-fold cross-validation for the Phenosense dataset was about 88% and for the Antivirogram dataset was about 79%. Thus, the PASS-based algorithm may be used for prediction of the amino acid substitutions associated with the resistance of HIV-1 based on open data. The computational approach for the prediction of HIV-1 associated resistance can be useful for the selection of RT inhibitors for the treatment of HIV infected patients in the clinical practice. Prediction of the HIV-1 RT associated resistance can be useful for the development of new anti-HIV drugs active against the resistant variants of RT. Therefore, we propose that this study can be potentially useful for anti-HIV drug development.

scholarly journals Anti-(human immunodeficiency virus) activity of polyoxotungstates and their inhibition of human immunodeficiency virus reverse transcriptase

1995 ◽  
Vol 307 (1) ◽  
pp. 129-134 ◽  
Author(s):  
P S Moore ◽  
C J Jones ◽  
N Mahmood ◽  
I G Evans ◽  
M Goff ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Polymerase Activity ◽  
Similar Degree ◽  
Hiv Reverse Transcriptase ◽  
Viral Activity ◽  
Immunodeficiency Virus ◽  
Deoxynucleoside Triphosphate ◽  
Dna Template ◽  
Hiv 1

Heteropolyoxotungstates of the Keggin class containing different heteroatoms were tested for inhibition of two strains of human immunodeficiency virus 1 (HIV-1); they exhibited varying antiviral activity. Compounds containing boron were inactive, only one of those containing phosphorus showed selective anti-viral activity, whereas all silicon-containing compounds exhibited significant anti-viral activity in C8166 cells infected with the IIIB strain. Their effectiveness was some 10-fold higher in JM cells with selectivity indices of about 2000. The silicotungstates were effective inhibitors of HIV reverse transcriptase, showing greater inhibition with RNA/DNA template primers than with DNA/DNA template.primer. Kinetic analysis demonstrated that they inhibit the enzyme by different mechanisms, as, of the four compounds examined, two competed with template.primer and two competed with deoxynucleoside triphosphate. Inhibition of DNA polymerase activity by these compounds was compared using polymerases from different sources, including human; although not necessarily most specific for HIV-1 reverse transcriptase, they did not inhibit all DNA polymerases to a similar degree.

Phaseococcin, an antifungal protein with antiproliferative and anti-HIV-1 reverse transcriptase activities from small scarlet runner beans

2005 ◽  
Vol 83 (2) ◽  
pp. 212-220 ◽  
Author(s):  
Patrick H.K Ngai ◽  
T B Ng
Keyword(s):  
Reverse Transcriptase ◽  
Gel Filtration ◽  
Leukemia Cell ◽  
Deae Cellulose ◽  
Antifungal Protein ◽  
Bacillus Species ◽  
Mouse Splenocytes ◽  
Antifungal Proteins ◽  
Reticulocyte Lysate ◽  
Hiv 1

From the seeds of small scarlet runner beans (Phaseolus coccineus 'Minor'), an antifungal protein with an N-terminal sequence homologous to those of defensins was isolated. The antifungal protein bound to Affi-gel blue gel and Mono S but it did not bind to DEAE-cellulose. It was further purified by gel filtration on a Superdex peptide column. It exhibited a molecular mass of 5422 Da as determined by mass spectrometry. The protein, designated as phaseococcin, suppressed mycelial growth in a number of fungi including Botrytis cinerea, Coprinus comatus, Fusarium oxysporum, Mycosphaerella arachidicola, Physalospora piricola, and Rhizoctonia solani. It also inhibited proliferation in several Bacillus species and the leukemia cell lines HL60 and L1210 and curtailed the activity of HIV-1 reverse transcriptase. It did not affect proliferation of mouse splenocytes and neither did it inhibit protein synthesis in a cell-free rabbit reticulocyte lysate system.Key words: antifungal proteins, runner beans, antiproliferative.

Structure and conformational analysis of the anti-HIV reverse transcriptase inhibitor AZT using MP2 and DFT methods. Differences with the natural nucleoside thymidine. Simulation of the 1st phosphorylation step with ATP

2014 ◽  
Vol 16 (45) ◽  
pp. 24763-24783 ◽  
Author(s):  
M. Alcolea Palafox
Keyword(s):  
Proton Transfer ◽  
Conformational Analysis ◽  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Transfer Mechanism ◽  
Hiv Reverse Transcriptase ◽  
Dft Methods ◽  
Reverse Transcriptase Inhibitor ◽  
Anti Hiv ◽  
Hiv 1

A proton-transfer mechanism is proposed for the first phosphorylation step of the nucleoside HIV-1 reverse transcriptase inhibitor AZT (3′-azido-3′ deoxythymidine) by interacting with ATP.

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