4-Thio-uridylate (UD29) interferes with the function of protein –SH and inhibits HIV replication in vitro

Beck, Zoltán; Kis, Andrea; Berényi, E; Kovács, P.; Fésüs, László; Aradi, J.

doi:10.1016/s1734-1140(09)70042-8

Cited by 5 publications

(6 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to conformational changes in cell surface receptors, coreceptors of HIV and viral envelope proteins, redox changes in these proteins are also required for successful HIV-1 entry and infection. Several inhibitors of protein disulfide isomerase (PDI) as well as cell-surface-thiol interacting agents including thioredoxin, influence HIV infection [14,15] indicating that redox processes active in viral entry could be potential targets for treatment of HIV infection, as we and others reported earlier [14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 79%

“…In this paper we extend the earlier study on the antiretroviral activity of 4-thio-uridylate (designated as UD29) [16] measuring its inhibitory activity in cell infectivity assays.…”

Section: Introductionmentioning

confidence: 81%

“…1) contains a reactive -SH group. It was shown earlier that UD29 is an inhibitor of glyceraldehyde-phosphate dehydrogenase (GAPDH) [16], likely interfering with the function of the essential -SH group in the active centre of the enzyme. The interfering effect of the -SH group of the nucleotide with protein -SHs could be the bases of the HIV entry inhibitory activity of UD29, verified by our time-of-addition experiment.…”

Section: Discussionmentioning

confidence: 99%

“…A 20 mM (6.66 mg/ml) aqueous stock solution of UD29 was prepared and kept at -20º C. It was diluted to the required concentration with tissue culture media before use. In UD29 the 4-thiono group has a propensity toward tautomeric conversion to form a reactive -SH, which may affect redox processes [16] (see Fig. 1).…”

Section: Preparation Of Thiolated Uridylate (S 4 Ump Ud29)mentioning

confidence: 99%

See 3 more Smart Citations

Antiretroviral effect of 4-thio-uridylate against human immunodeficiency virus type 1

Kanizsai

Ghidán

Ongrádi

et al. 2012

Acta Microbiologica Et Immunologica Hungarica

View full text Add to dashboard Cite

Antiretroviral effect of thiolated nucleotide 4-thio-uridylate (S 4 UMP, designated as UD29) against human immunodeficiency virus type 1 (HIV-1) have been quantitatively determined in cell-based viral infectivity assays. In syntitium inhibition assay on MT-2 human T-cell line UD29 prevented cell fusion and formation of syntitia induced by HIV-1 IIIB with IC 50 values of 11.7 µg/ml. In a single-cycle viral infection assay (MAGI assay) UD29 proved to have a potent inhibitory effect against HIV-1 IIIB on HeLaCD4-LTR/b-gal cells, which was dose dependent with IC 50 values of 4.75 µg/ml and IC 90 of 39.7 µg/ml. UD29 showed a most prominent antiviral effect when administered 30 min prior HIV-1 infection. As HIV entry requires thiol/disulfide exchange process, results suggest that reactive -SH group of enol-form of the thiolated nucleotide may interfere with the function of cell surface proteins. UD29 cannot penetrate into cells and may have an interactive role in redox processes active in viral entry.

show abstract

Section: Introductionmentioning

confidence: 79%

“…In this paper we extend the earlier study on the antiretroviral activity of 4-thio-uridylate (designated as UD29) [16] measuring its inhibitory activity in cell infectivity assays.…”

Section: Introductionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Preparation Of Thiolated Uridylate (S 4 Ump Ud29)mentioning

confidence: 99%

See 2 more Smart Citations

Antiretroviral effect of 4-thio-uridylate against human immunodeficiency virus type 1

Kanizsai

Ghidán

Ongrádi

et al. 2012

Acta Microbiologica Et Immunologica Hungarica

View full text Add to dashboard Cite

show abstract

“…A mononucleotide, 4-thiouridylate showed anti-proliferative activity on various leukemic and solid tumour cell lines [19,41]. Since 4-thiouridylate, as a nucleotide, cannot penetrate into the cells, it must exert its activity at the cell surface.…”

Section: Page 16 Of 33 Cancer Chemotherapy and Pharmacologymentioning

confidence: 99%

Myelotoxicity of carboplatin is increased in vivo in db/db mice, the animal model of obesity-associated diabetes mellitus

Géresi

Megyeri

Szabo

et al. 2015

Cancer Chemother Pharmacol

Self Cite

View full text Add to dashboard Cite

PurposeSome authors observed increased carboplatin-associated myelotoxicity in obese patients which was exclusively attributed to elevated AUC. To investigate the potential contribution of functional changes of cells primarily responsible for myelopoiesis, granulocyte-macrophage progenitors (CFU-GM) were studied in obesity-associated diabetes mellitus (DMT2). MethodsThe most frequently used animal model of human obesity with DMT2 is db/db mouse. Cellularity, frequency of CFU-GM and total CFU-GM content of femoral bone marrow was measured after 100 mg/kg dose of carboplatin in vivo. To exclude influence of pharmacokinetic changes direct toxicity of carboplatin on CFU-GM was also determined in vitro and was compared with other anticancer agents, namely doxorubicin, 5-fluorouracil and 4-thiouridylate. ResultsAfter intraperitoneal administration of carboplatin, each measured characteristics of bone marrow function were more significantly suppressed and the induced neutropenia were more serious in db/db mice than in the controls. The increased myelotoxicity seemed to be a direct effect on myeloid progenitor cells since their increased in vitro sensitivity was found in db/db mice. This was not specific for carboplatin, a similar double to 5-fold increase in myelotoxicity of each cytotoxic drug with different mechanism of action was observed. Four-thiouridylate, a promising antileukemic molecule with good therapeutic index, was by far the least toxic for CFU-GM of db/db mice.Conclusions A serious disorder of CFU-GM progenitors was suggested in obese mice with DMT2, which eventually might lead to more severe myelotoxicity and neutropenia. Weight loss and normalization of glucose homeostasis may be important before chemotherapy of malignant diseases in obesity with DMT2.

show abstract

New Approach for Inhibition of HIV Entry: Modifying CD4 Binding Sites by Thiolated Pyrimidine Derivatives

Kanizsai

Ongrádi

Aradi

et al. 2016

Pathol. Oncol. Res.

View full text Add to dashboard Cite

Thiolated pyrimidine derivatives have been synthetized and their antiretroviral effect against human immunodeficiency virus type 1 (HIV-1IIIB) and HIV-1 chimeric pseudovirions have been quantitatively determined in cell-based viral infectivity assays including syncytium inhibition assay as well as a single-cycle viral infection assay on HeLaCD4-LTR/ß-gal cells. Pseudotype virions prepared bearing HIV-1 envelope preference for CCR5 coreceptor, CXCR4 coreceptor or for both, respectively, with a HIV-1 core containing luciferase reporter gene were able to infect susceptible cells but are replication defective so unable to replicate in the cells . Data indicate that thiolated pyrimidine derivatives inhibited effectively virally induced cell fusion in vitro as well as infectivity of primary HIV-1IIIB strain and HIV-1 pseudovirions using chemokine receptors CCR5 or CXCR4 or both for virus entry a dose dependent manner. Inhibition was selective, depended on the pseudovirus coreceptor preference. Our results suggest that some of these sulfur containing pyrimidines interact with redoxactive -SH groups required for successful HIV entry, including a redox active disulfide in the CD4 molecule as well as -SH groups in HIV viral envelope gp120. This mode of action is unique representing a new class of potential HIV entry inhibitors.

show abstract

4-Thio-uridylate (UD29) interferes with the function of protein –SH and inhibits HIV replication in vitro

Cited by 5 publications

References 11 publications

Antiretroviral effect of 4-thio-uridylate against human immunodeficiency virus type 1

Antiretroviral effect of 4-thio-uridylate against human immunodeficiency virus type 1

Myelotoxicity of carboplatin is increased in vivo in db/db mice, the animal model of obesity-associated diabetes mellitus

New Approach for Inhibition of HIV Entry: Modifying CD4 Binding Sites by Thiolated Pyrimidine Derivatives

Contact Info

Product

Resources

About