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1.
J Transl Med ; 22(1): 426, 2024 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-38711085

RESUMEN

BACKGROUND: Programmed cell death 1 (PD-1) belongs to immune checkpoint proteins ensuring negative regulation of the immune response. In non-small cell lung cancer (NSCLC), the sensitivity to treatment with anti-PD-1 therapeutics, and its efficacy, mostly correlated with the increase of tumor infiltrating PD-1+ lymphocytes. Due to solid tumor heterogeneity of PD-1+ populations, novel low molecular weight anti-PD-1 high-affinity diagnostic probes can increase the reliability of expression profiling of PD-1+ tumor infiltrating lymphocytes (TILs) in tumor tissue biopsies and in vivo mapping efficiency using immune-PET imaging. METHODS: We designed a 13 kDa ß-sheet Myomedin scaffold combinatorial library by randomization of 12 mutable residues, and in combination with ribosome display, we identified anti-PD-1 Myomedin variants (MBA ligands) that specifically bound to human and murine PD-1-transfected HEK293T cells and human SUP-T1 cells spontaneously overexpressing cell surface PD-1. RESULTS: Binding affinity to cell-surface expressed human and murine PD-1 on transfected HEK293T cells was measured by fluorescence with LigandTracer and resulted in the selection of most promising variants MBA066 (hPD-1 KD = 6.9 nM; mPD-1 KD = 40.5 nM), MBA197 (hPD-1 KD = 29.7 nM; mPD-1 KD = 21.4 nM) and MBA414 (hPD-1 KD = 8.6 nM; mPD-1 KD = 2.4 nM). The potential of MBA proteins for imaging of PD-1+ populations in vivo was demonstrated using deferoxamine-conjugated MBA labeled with 68Galium isotope. Radiochemical purity of 68Ga-MBA proteins reached values 94.7-99.3% and in vitro stability in human serum after 120 min was in the range 94.6-98.2%. The distribution of 68Ga-MBA proteins in mice was monitored using whole-body positron emission tomography combined with computerized tomography (PET/CT) imaging up to 90 min post-injection and post mortem examined in 12 mouse organs. The specificity of MBA proteins was proven by co-staining frozen sections of human tonsils and NSCLC tissue biopsies with anti-PD-1 antibody, and demonstrated their potential for mapping PD-1+ populations in solid tumors. CONCLUSIONS: Using directed evolution, we developed a unique set of small binding proteins that can improve PD-1 diagnostics in vitro as well as in vivo using PET/CT imaging.


Asunto(s)
Tomografía de Emisión de Positrones , Receptor de Muerte Celular Programada 1 , Ingeniería de Proteínas , Humanos , Receptor de Muerte Celular Programada 1/metabolismo , Animales , Tomografía de Emisión de Positrones/métodos , Células HEK293 , Ratones , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Secuencia de Aminoácidos
2.
Cell Commun Signal ; 22(1): 261, 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38715108

RESUMEN

BACKGROUND: Interleukin-6 (IL-6) is a multifunctional cytokine that controls the immune response, and its role has been described in the development of autoimmune diseases. Signaling via its cognate IL-6 receptor (IL-6R) complex is critical in tumor progression and, therefore, IL-6R represents an important therapeutic target. METHODS: An albumin-binding domain-derived highly complex combinatorial library was used to select IL-6R alpha (IL-6Rα)-targeted small protein binders using ribosome display. Large-scale screening of bacterial lysates of individual clones was performed using ELISA, and their IL-6Rα blocking potential was verified by competition ELISA. The binding of proteins to cells was monitored by flow cytometry and confocal microscopy on HEK293T-transfected cells, and inhibition of signaling function was examined using HEK-Blue IL-6 reporter cells. Protein binding kinetics to living cells was measured by LigandTracer, cell proliferation and toxicity by iCELLigence and Incucyte, cell migration by the scratch wound healing assay, and prediction of binding poses using molecular modeling by docking. RESULTS: We demonstrated a collection of protein variants called NEF ligands, selected from an albumin-binding domain scaffold-derived combinatorial library, and showed their binding specificity to human IL-6Rα and antagonistic effect in HEK-Blue IL-6 reporter cells. The three most promising NEF108, NEF163, and NEF172 variants inhibited cell proliferation of malignant melanoma (G361 and A2058) and pancreatic (PaTu and MiaPaCa) cancer cells, and suppressed migration of malignant melanoma (A2058), pancreatic carcinoma (PaTu), and glioblastoma (GAMG) cells in vitro. The NEF binders also recognized maturation-induced IL-6Rα expression and interfered with IL-6-induced differentiation in primary human B cells. CONCLUSION: We report on the generation of small protein blockers of human IL-6Rα using directed evolution. NEF proteins represent a promising class of non-toxic anti-tumor agents with migrastatic potential.


Asunto(s)
Movimiento Celular , Proliferación Celular , Receptores de Interleucina-6 , Humanos , Proliferación Celular/efectos de los fármacos , Receptores de Interleucina-6/metabolismo , Movimiento Celular/efectos de los fármacos , Células HEK293 , Línea Celular Tumoral , Unión Proteica/efectos de los fármacos
3.
Nature ; 535(7612): 444-7, 2016 07 21.
Artículo en Inglés | MEDLINE | ID: mdl-27383794

RESUMEN

The chemical nature of the 5' end of RNA is a key determinant of RNA stability, processing, localization and translation efficiency, and has been proposed to provide a layer of 'epitranscriptomic' gene regulation. Recently it has been shown that some bacterial RNA species carry a 5'-end structure reminiscent of the 5' 7-methylguanylate 'cap' in eukaryotic RNA. In particular, RNA species containing a 5'-end nicotinamide adenine dinucleotide (NAD+) or 3'-desphospho-coenzyme A (dpCoA) have been identified in both Gram-negative and Gram-positive bacteria. It has been proposed that NAD+, reduced NAD+ (NADH) and dpCoA caps are added to RNA after transcription initiation, in a manner analogous to the addition of 7-methylguanylate caps. Here we show instead that NAD+, NADH and dpCoA are incorporated into RNA during transcription initiation, by serving as non-canonical initiating nucleotides (NCINs) for de novo transcription initiation by cellular RNA polymerase (RNAP). We further show that both bacterial RNAP and eukaryotic RNAP II incorporate NCIN caps, that promoter DNA sequences at and upstream of the transcription start site determine the efficiency of NCIN capping, that NCIN capping occurs in vivo, and that NCIN capping has functional consequences. We report crystal structures of transcription initiation complexes containing NCIN-capped RNA products. Our results define the mechanism and structural basis of NCIN capping, and suggest that NCIN-mediated 'ab initio capping' may occur in all organisms.


Asunto(s)
Coenzima A/metabolismo , NAD/metabolismo , Caperuzas de ARN/metabolismo , Iniciación de la Transcripción Genética , Adenosina Trifosfato/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Secuencia de Bases , ARN Polimerasas Dirigidas por ADN/metabolismo , Datos de Secuencia Molecular , Nucleótidos/química , Nucleótidos/metabolismo , Regiones Promotoras Genéticas/genética , Caperuzas de ARN/química , ARN Polimerasa II/metabolismo , Saccharomyces cerevisiae/enzimología , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Sitio de Iniciación de la Transcripción
4.
Eur J Biomed Res ; 2(3): 17-23, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37525697

RESUMEN

Whole-genome SARS-CoV-2 sequencing tools are crucial for tracking the COVID-19 pandemic. However, current techniques require sampling of actively infectious patients following COVID-19 testing to recover enough SARS-CoV-2 RNA from the nasopharyngeal passage, which rapidly clears during the first few weeks of infection. A prospective assessment of the viral genome sourced from recovered non-infectious patients would greatly facilitate epidemiological tracking. Thus, we developed a protocol to isolate and sequence the genome of SARS-CoV-2 from stool samples of post-acute SARS-CoV-2 patients, at timepoints ranging from 10-120 days after onset of symptoms. Stool samples were collected from patients at varying timepoints post-convalescence, and viral DNA was isolated and sequenced using the QIAamp Viral RNA Mini Kit (Qiagen Inc.) and Ion Ampliseq™ Library Kit Plus (Life Technologies Corporation). Capacity of neutralizing antibodies in patient plasma was tested using a Luminex panel (Coronavirus Ig Total Human 11-Plex ProcartaPlex™ Panel, ThermoFisher). Of 64 samples obtained from post-acute patients, 21 (32.8%) yielded sufficient material for whole-genome sequencing. This allowed us to identify widely divergent phylogenetic relativity of the SARS-CoV-2 genome from post-acute patients living in the same households and infected around the same time. Additionally, we observed that individuals who recovered from infection expressed varying degrees of antibodies against SARS-CoV-2 structural proteins that corresponded to distinct variants. Interestingly, we identified a novel point mutation in the viral genome where infected patients expressed antibodies with a significantly reduced capacity to neutralize the virus in vitro relative to that of those infected with the wild-type strain. Altogether, we demonstrate a protocol to successfully sequence the SARS-CoV-2 genome from stool samples from patients up to 4 months post-infection, which can be applied to studies that assess the relationship between variants and immune response post-hoc and safe monitoring of the SARS-CoV-2 genome during the pandemic.

5.
Bioorg Med Chem Lett ; 22(1): 181-5, 2012 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-22169265

RESUMEN

To determine the influence of internucleotide linkage and sugar ring conformation, and the role of 5'-terminal phosphate, on the activation of human RNase L, a series of 2'- and 5'-O-methylphosphonate-modified tetramers were synthesized from appropriate monomeric units and evaluated for their ability to activate human RNase L. Tetramers pAAAp(c)X modified by ribo, arabino or xylo 5'-phosphonate unit p(c)X activated RNase L with efficiency comparable to that of natural activator. Moreover, incorporation of phosphonate linkages ensured the stability against cleavage by nucleases. The substitution of 5'-terminal phosphate for 5'-terminal phosphonate in tetramer p(c)XAAA afforded tetramers with excellent activation efficiency and with complete stability against cleavage by phosphomonoesterases.


Asunto(s)
Nucleótidos de Adenina/química , Endorribonucleasas/química , Oligorribonucleótidos/química , Organofosfonatos/química , Animales , Sistema Libre de Células , Química Farmacéutica/métodos , Dimerización , Diseño de Fármacos , Transferencia Resonante de Energía de Fluorescencia/métodos , Humanos , Ratones , Modelos Químicos , Factores de Tiempo
6.
Org Biomol Chem ; 9(8): 2856-60, 2011 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-21365121

RESUMEN

The synthesis of the novel nucleotide analogues 5'-deoxynucleoside-5'-S-methylphosphonates, starting from 5'-deoxy-5'-haloribonucleosides, 5'-O-tosylribonucleosides, and 2'-O-triflylnucleosides, is described. The phosphonothiolation of these compounds was achieved using S-(diisopropylphosphonomethyl)isothiouronium tosylate, a new, odourless, and efficient equivalent of mercaptomethylphosphonate. The thiolate anion of mercaptomethylphosphonate was generated in situ from the isothiouronium salt in both protic and aprotic solvents using two equivalents of sodium iso-propoxide. The prepared nucleoside 5'-S-methylphosphonates were deprotected, and the free phosphonic acids were transformed into diphosphoryl derivatives (the NTP analogues). Both mononucleotides and NTP analogues were studied as substrates/inhibitors of several enzymes that are involved in the nucleoside/nucleotide metabolism.


Asunto(s)
Isotiuronio/análogos & derivados , Nucleósidos/química , Compuestos Organofosforados/síntesis química , Compuestos de Tosilo/química , Isotiuronio/química , Modelos Moleculares , Estructura Molecular
7.
Biosens Bioelectron ; 172: 112784, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33161292

RESUMEN

Cell immunocapture microfluidic devices represent a rapidly developing field with many potential applications in medical diagnostics. The core of such approach lies in the cell binding to antibody coated surfaces through their surface receptors. Here we show, that the small recombinant protein binders (PBs) can be used for this purpose as well, with the advantage of their constructional flexibility, possibility of fusion with range of tags and cheap mass production. For this purpose, two different PBs derived from Albumin Binding Domain (ABDwt) of streptococcal protein G, so called REX and ARS ligands with proved high affinity and selectivity to the human interleukin-23 (IL-23R) and IL-17 receptor A were used. Four PBs variants recognizing two different epitopes on two different receptors and two PBs variants binding to the same epitope on one receptor but having different peptide spacer with Avitag sequence necessary for their immobilization on sensor surface were tested for cell-capture efficiency. The glass microfluidic Y-system with planar immunocapture channel working in so-called stop-flow dynamic regime was designed. Up to 60-74% immunocapture efficiency of model THP-1 cells on REX/ARS surfaces and practically no cell binding on control ABDwt surfaces was achieved. Moreover, the specific immunocapture of THP-1 cells from mixture with IL-17RA negative DU-145 cells was demonstrated. We discuss the role of the epitope, affinity and immobilization spacer of PBs as well as the influence of stop-flow dynamic regime on the effectivity of THP-1 cell immunocapture. Results can be further exploited in design of microfluidic devices for rare cells immunocapture.


Asunto(s)
Técnicas Biosensibles , Células Neoplásicas Circulantes , Humanos , Microfluídica , Receptores de Interleucina-17 , Proteínas Recombinantes/genética
8.
Bioorg Med Chem Lett ; 20(3): 862-5, 2010 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-20053558

RESUMEN

Structurally diverse, sugar-modified, thymine-containing nucleoside phosphonic acids were evaluated for their ability to inhibit thymidine phosphorylase (TP, EC 2.4.2.4) purified from spontaneous T-cell lymphomas of an inbred Sprague-Dawley rat strain. From a large set of tested compounds, among them a number of pyrrolidine-based derivatives, 10 nucleotide analogues with IC(50) values below 1 microM were selected. Out of them, four compounds strongly inhibited the enzyme with IC(50) values lying in a range of 11-45 nM. These most potent compounds might be bi-substrate analogues.


Asunto(s)
Linfoma de Células T/enzimología , Nucleósidos/química , Organofosfonatos/química , Timidina Fosforilasa/antagonistas & inhibidores , Animales , Relación Dosis-Respuesta a Droga , Humanos , Concentración 50 Inhibidora , Nucleósidos/farmacología , Organofosfonatos/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Timidina Fosforilasa/metabolismo
9.
FEMS Microbiol Rev ; 41(2): 131-138, 2017 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-27799279

RESUMEN

RNA polymerase (RNAP) is the central enzyme of transcription of the genetic information from DNA into RNA. RNAP recognizes four main substrates: ATP, CTP, GTP and UTP. Experimental evidence from the past several years suggests that, besides these four NTPs, other molecules can be used to initiate transcription: (i) ribooligonucleotides (nanoRNAs) and (ii) coenzymes such as NAD+, NADH, dephospho-CoA and FAD. The presence of these molecules at the 5΄ ends of RNAs affects the properties of the RNA. Here, we discuss the expanding portfolio of molecules that can initiate transcription, their mechanism of incorporation, effects on RNA and cellular processes, and we present an outlook toward other possible initiation substrates.


Asunto(s)
Iniciación de la Transcripción Genética/fisiología , Coenzimas , Oligonucleótidos
10.
J Med Chem ; 60(14): 6098-6118, 2017 07 27.
Artículo en Inglés | MEDLINE | ID: mdl-28654257

RESUMEN

The increase in the number of bacterial strains resistant to known antibiotics is alarming. In this study we report the synthesis of novel compounds termed Lipophosphonoxins II (LPPO II). We show that LPPO II display excellent activities against Gram-positive and -negative bacteria, including pathogens and multiresistant strains. We describe their mechanism of action-plasmatic membrane pore-forming activity selective for bacteria. Importantly, LPPO II neither damage nor cross the eukaryotic plasmatic membrane at their bactericidal concentrations. Further, we demonstrate LPPO II have low propensity for resistance development, likely due to their rapid membrane-targeting mode of action. Finally, we reveal that LPPO II are not toxic to either eukaryotic cells or model animals when administered orally or topically. Collectively, these results suggest that LPPO II are highly promising compounds for development into pharmaceuticals.


Asunto(s)
Antibacterianos/química , Uridina Monofosfato/análogos & derivados , Animales , Antibacterianos/síntesis química , Antibacterianos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Membrana Celular/metabolismo , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Farmacorresistencia Bacteriana Múltiple , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Humanos , Membrana Dobles de Lípidos/química , Masculino , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Fosfolípidos/química , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacología , Conejos , Pruebas de Irritación de la Piel , Estereoisomerismo , Relación Estructura-Actividad , Uridina Monofosfato/síntesis química , Uridina Monofosfato/química , Uridina Monofosfato/farmacología
11.
PLoS One ; 10(12): e0145918, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26716439

RESUMEN

The advantages offered by established antibiotics in the treatment of infectious diseases are endangered due to the increase in the number of antibiotic-resistant bacterial strains. This leads to a need for new antibacterial compounds. Recently, we discovered a series of compounds termed lipophosphonoxins (LPPOs) that exhibit selective cytotoxicity towards Gram-positive bacteria that include pathogens and resistant strains. For further development of these compounds, it was necessary to identify the mechanism of their action and characterize their interaction with eukaryotic cells/organisms in more detail. Here, we show that at their bactericidal concentrations LPPOs localize to the plasmatic membrane in bacteria but not in eukaryotes. In an in vitro system we demonstrate that LPPOs create pores in the membrane. This provides an explanation of their action in vivo where they cause serious damage of the cellular membrane, efflux of the cytosol, and cell disintegration. Further, we show that (i) LPPOs are not genotoxic as determined by the Ames test, (ii) do not cross a monolayer of Caco-2 cells, suggesting they are unable of transepithelial transport, (iii) are well tolerated by living mice when administered orally but not peritoneally, and (iv) are stable at low pH, indicating they could survive the acidic environment in the stomach. Finally, using one of the most potent LPPOs, we attempted and failed to select resistant strains against this compound while we were able to readily select resistant strains against a known antibiotic, rifampicin. In summary, LPPOs represent a new class of compounds with a potential for development as antibacterial agents for topical applications and perhaps also for treatment of gastrointestinal infections.


Asunto(s)
Antibacterianos/farmacología , Nucleósidos de Pirimidina/farmacología , Animales , Antibacterianos/química , Antibacterianos/farmacocinética , Bacillus subtilis/efectos de los fármacos , Bacillus subtilis/crecimiento & desarrollo , Bacillus subtilis/metabolismo , Transporte Biológico Activo , Células CACO-2 , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Permeabilidad de la Membrana Celular/efectos de los fármacos , Descubrimiento de Drogas , Estabilidad de Medicamentos , Enterococcus faecalis/efectos de los fármacos , Enterococcus faecalis/crecimiento & desarrollo , Femenino , Bacterias Grampositivas/efectos de los fármacos , Bacterias Grampositivas/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Microscopía Electrónica de Transmisión , Estructura Molecular , Unión Proteica , Nucleósidos de Pirimidina/química , Nucleósidos de Pirimidina/farmacocinética , Streptococcus agalactiae/efectos de los fármacos , Streptococcus agalactiae/crecimiento & desarrollo
12.
Eur J Med Chem ; 74: 145-68, 2014 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-24462848

RESUMEN

A series of conformationally constrained uridine-based nucleoside phosphonic acids containing annealed 1,3-dioxolane and 1,4-dioxane rings and their "open-structure" isosteres were synthesized and evaluated as potential multisubstrate-like inhibitors of the human recombinant thymidine phosphorylase (TP, EC 2.4.2.4) and TP obtained from peripheral blood mononuclear cells (PBMC). From a large set of tested nucleoside phosphonic acids, several potent compounds were identified that exhibited Ki values in the range of 0.048-1 µM. The inhibition potency of the studied compounds strongly depended on the degree of conformational flexibility of the phosphonate moiety, the stereochemical arrangement of the sugar-phosphonate component, and the substituent at position 5 of the pyrimidine nucleobase.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Ácidos Fosforosos/farmacología , Nucleósidos de Pirimidina/farmacología , Timidina Fosforilasa/antagonistas & inhibidores , Humanos , Conformación Molecular , Ácidos Fosforosos/química , Relación Estructura-Actividad
13.
J Med Chem ; 55(4): 1612-21, 2012 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-22264015

RESUMEN

A complete series of pyrrolidine nucleotides, (3R)- and (3S)-3-(guanin-9-yl)pyrrolidin-1-N-ylcarbonylphosphonic acids and (3S,4R)-, (3R,4S)-, (3S,4S)-, and (3R,4R)-4-(guanin-9-yl)-3-hydroxypyrrolidin-1-N-ylcarbonylphosphonic acids, were synthesized and evaluated as potential inhibitors of purine nucleoside phosphorylase (PNP) isolated from peripheral blood mononuclear cells (PBMCs) and cell lines of myeloid and lymphoid origin. Two compounds, (S)-3-(guanin-9-yl)pyrrolidin-1-N-ylcarbonylphosphonic acid (2a) and (3S,4R)-4-(guanin-9-yl)-3-hydroxypyrrolidin-1-N-ylcarbonylphosphonic acid (6a), were recognized as nanomolar competitive inhibitors of PNP isolated from cell lines with K(i) values within the ranges of 16-100 and 10-24 nM, respectively. The low (MESG)K(i) and (Pi)K(i) values of both compounds for PNP isolated from PBMCs suggest that these compounds could be bisubstrate inhibitors that occupy both the phosphate and nucleoside binding sites of the enzyme.


Asunto(s)
Nucleótidos de Guanina/síntesis química , Guanina/análogos & derivados , Guanina/síntesis química , Organofosfonatos/síntesis química , Purina-Nucleósido Fosforilasa/antagonistas & inhibidores , Pirrolidinas/síntesis química , Línea Celular Tumoral , Guanina/química , Nucleótidos de Guanina/química , Humanos , Leucocitos Mononucleares/enzimología , Organofosfonatos/química , Ácidos Fosforosos , Purina-Nucleósido Fosforilasa/química , Pirrolidinas/química , Estereoisomerismo , Relación Estructura-Actividad
14.
Nucleosides Nucleotides Nucleic Acids ; 27(12): 1211-4, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19003566

RESUMEN

Substrate specificity of E. coli thymidine phosphorylase to pyrimidine nucleoside modified at 5'-, 3'-, and 2'-positions of sugar moiety has been studied. Equilibrium (K(eq)) and kinetics constants of phosphorolysis reaction of nucleosides were measured. The most important hydrogen bonds in enzyme-substrate complex have been determined.


Asunto(s)
Proteínas de Escherichia coli/metabolismo , Escherichia coli/enzimología , Timidina Fosforilasa/metabolismo , Enlace de Hidrógeno , Cinética , Especificidad por Sustrato
15.
Nucleic Acids Symp Ser (Oxf) ; (52): 665-6, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18776555

RESUMEN

A number of structurally diverse nucleoside phosphonic acids have been tested against human recombinant thymidine phosphorylase and human platelets supernatant using 2'-deoxy-5-nitrouridine as the substrate. We have selected several inhibitors working at micromolar level as lead structures for further evaluation.


Asunto(s)
Inhibidores Enzimáticos/química , Nucleósidos/química , Nucleósidos/farmacología , Organofosfonatos/química , Timidina Fosforilasa/antagonistas & inhibidores , Animales , Plaquetas/enzimología , Células CHO , Cricetinae , Cricetulus , Inhibidores Enzimáticos/farmacología , Humanos , Relación Estructura-Actividad , Timidina Fosforilasa/química
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