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1.
Antimicrob Agents Chemother ; : e0002224, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38624217

RESUMO

Candida parapsilosis has recently emerged as a major threat due to the worldwide emergence of fluconazole-resistant strains causing clonal outbreaks in hospitals and poses a therapeutic challenge due to the limited antifungal armamentarium. Here, we used precise genome editing using CRISPR-Cas9 to gain further insights into the contribution of mutations in ERG11, ERG3, MRR1, and TAC1 genes and the influence of allelic dosage to antifungal resistance in C. parapsilosis. Seven of the most common amino acid substitutions previously reported in fluconazole-resistant clinical isolates (including Y132F in ERG11) were engineered in two fluconazole-susceptible C. parapsilosis lineages (ATCC 22019 and STZ5). Each mutant was then challenged in vitro against a large array of antifungals, with a focus on azoles. Any possible change in virulence was also assessed in a Galleria mellonella model. We successfully generated a total of 19 different mutants, using CRISPR-Cas9. Except for R398I (ERG11), all remaining amino acid substitutions conferred reduced susceptibility to fluconazole. However, the impact on fluconazole in vitro susceptibility varied greatly according to the engineered mutation, the stronger impact being noted for G583R acting as a gain-of-function mutation in MRR1. Cross-resistance with newer azoles, non-medical azoles, but also non-azole antifungals such as flucytosine, was occasionally noted. Posaconazole and isavuconazole remained the most active in vitro. Except for G583R, no fitness cost was associated with the acquisition of fluconazole resistance. We highlight the distinct contributions of amino acid substitutions in ERG11, ERG3, MRR1, and TAC1 genes to antifungal resistance in C. parapsilosis.

2.
Molecules ; 26(21)2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34770981

RESUMO

Pim kinases (proviral integration site for Moloney murine leukemia virus kinases) are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation and survival. Thus, Pim kinases are validated as targets for antitumor therapy. In this context, our combined efforts in natural product-inspired library generation and screening furnished very promising dibenzo[b,d]furan derivatives derived from cercosporamide. Among them, lead compound 44 was highlighted as a potent Pim-1/2 kinases inhibitor with an additional nanomolar IC50 value against CLK1 (cdc2-like kinases 1) and displayed a low micromolar anticancer potency towards the MV4-11 (AML) cell line, expressing high endogenous levels of Pim-1/2 kinases. The design, synthesis, structure-activity relationship, and docking studies are reported herein and supported by enzyme, cellular assays, and Galleria mellonella larvae testing for acute toxicity.


Assuntos
Antineoplásicos/farmacologia , Benzofuranos/química , Benzofuranos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Benzofuranos/síntese química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Mariposas , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Células Tumorais Cultivadas
3.
J Enzyme Inhib Med Chem ; 35(1): 398-403, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31899979

RESUMO

(2-(2,4-Dichlorophenyl)-3-(1H-indol-1-yl)-1-(1,2,4-1H-triazol-1-yl)propan-2-ol (8 g), a new 1,2,4-triazole-indole hybrid molecule, showed a broad-spectrum activity against Candida, particularly against low fluconazole-susceptible species. Its activity was higher than fluconazole and similar to voriconazole on C. glabrata (MIC90 = 0.25, 64 and 1 µg/mL, respectively), C. krusei (MIC90 = 0.125, 64 and 0.125 µg/mL, respectively) and C. albicans (MIC90 = 0.5, 8 and 0.25 µg/mL, respectively). The action mechanisms of 8 g were also identified as inhibition of ergosterol biosynthesis and phospholipase A2-like activity. At concentration as low as 4 ng/mL, 8g inhibited ergosterol production by 82% and induced production of 14a-methyl sterols, that is comparable to the results obtained with fluconazole at higher concentration. 8 g demonstrated moderate inhibitory effect on phospholipase A2-like activity being a putative virulence factor. Due to a low MRC5 cytotoxicity, this compound presents a high therapeutic index. These results pointed out that 8 g is a new lead antifungal candidate with potent ergosterol biosynthesis inhibition.


Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Indóis/farmacologia , Triazóis/farmacologia , Animais , Antifúngicos/química , Candida/enzimologia , Candida/metabolismo , Linhagem Celular , Ergosterol/antagonistas & inibidores , Ergosterol/biossíntese , Feminino , Humanos , Indóis/química , Camundongos , Testes de Sensibilidade Microbiana , Especificidade da Espécie , Triazóis/química
4.
Bioorg Med Chem Lett ; 28(13): 2250-2255, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29853332

RESUMO

In a context of growing resistance to classical antifungal therapy, the design of new drugs targeting alternative pathways is highly expected. Benzofuro[3,2-d]pyrimidine derivatives, derived from (-)-cercosporamide, were synthesized and evaluated as potential Candida albicans PKC inhibitors in the aim of restoring susceptibility to azole treatment. Co-administration assay of benzofuropyrimidinedione 23 and fluconazole highlighted a synergistic effect on inhibition of cell growth of a Candida albicans resistant strain.


Assuntos
Antifúngicos/farmacologia , Benzofuranos/farmacologia , Farmacorresistência Fúngica/efeitos dos fármacos , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinonas/farmacologia , Antifúngicos/síntese química , Ascomicetos/química , Benzofuranos/síntese química , Biofilmes/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Candida albicans/enzimologia , Sinergismo Farmacológico , Fluconazol/síntese química , Fluconazol/farmacologia , Células HeLa , Humanos , Inibidores de Proteínas Quinases/síntese química , Pirimidinonas/síntese química
5.
Genes Dev ; 23(24): 2915-24, 2009 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-20008939

RESUMO

Mechanisms of telomere replication remain poorly defined. It has been suggested that G-rich telomeric strand replication by lagging mechanisms requires, in a stochastic way, the WRN protein. Here we show that this requirement is more systematic than previously thought. Our data are compatible with a situation in which, in the absence of WRN, DNA synthesis at replication forks is uncoupled, thus allowing replication to continue on the C strand, while single G strands accumulate. We also show that in cells in which both WRN and POT1 are limiting, both G- and C-rich telomeric strands shorten, suggesting a complete replication block. Under this particular condition, expression of a fragment spanning the two POT1-OB (oligonucleotide-binding) fold domains is able to restore C (but not G) strand replication, suggesting that binding of POT1 to the lagging strand allows DNA synthesis uncoupling in the absence of WRN. Furthermore, in vitro experiments indicate that purified POT1 has a higher affinity for the telomeric G-rich strand than purified RPA. We propose a model in which the relative enrichments of POT1 versus RPA on the telomeric lagging strand allows or does not allow uncoupling of DNA synthesis at the replication fork. Our study reveals an unanticipated role for hPOT1 during telomere replication.


Assuntos
Citosina , Replicação do DNA/genética , Exodesoxirribonucleases/genética , RecQ Helicases/genética , Proteínas de Ligação a Telômeros/metabolismo , Telômero/genética , Citosina/química , Exodesoxirribonucleases/deficiência , Guanina/química , Humanos , Hibridização in Situ Fluorescente , RecQ Helicases/deficiência , Complexo Shelterina , Helicase da Síndrome de Werner
6.
Methods Mol Biol ; 2704: 143-156, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37642842

RESUMO

Sterols are the main components of the fungal membrane. Their study can be used to describe the chemical biodiversity among the strains and species or to work on antifungal treatment. Those molecules can be analyzed by gas chromatography coupled with mass spectrometry (GC-MS) as free molecules or after derivation as acetate or trimethylsilyl ether (TMSi). Here we describe how to extract sterols from fungal biomass according to its physiological form and the culture conditions (liquid and solid media). The different methodologies that can be used to obtain free sterols, acetate, and/or TMSi derivatives are presented. Identification keys using the fragmentation at 70 eV are also described.


Assuntos
Fitosteróis , Esteróis , Cromatografia Gasosa-Espectrometria de Massas , Antifúngicos , Biodiversidade
7.
Future Microbiol ; 18: 1225-1233, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37882752

RESUMO

Aim: To evaluate antifungal potential of 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine hybrids based on thiosemicarbazones and thiazolidinediones against pathogenic Sporothrix species. Methods: Antifungal activity of nine compounds were assessed by broth microdilution. Interactions between active compounds and itraconazole were evaluated by the checkerboard assay using non-wild-type isolates. Cytotoxicity of the compounds was determined. Results: Four C-3 substituted analogs showed antifungal activity, unrelated to thiosemicarbazone or thiazolidinedione functions. Synergistic interactions between the four compounds and itraconazole, and low toxicity on mouse fibroblast cells were observed. Activity of 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine hybrids against Sporothrix depended on the substitution on the imidazopyrazine ring. Conclusion: Antifungal potential, overcoming itraconazole resistance and low toxicity indicate the possible use of that series of compounds in a therapeutic alternative for treatment of sporotrichosis.


Assuntos
Sporothrix , Tiazolidinedionas , Tiossemicarbazonas , Animais , Camundongos , Antifúngicos/farmacologia , Itraconazol/farmacologia , Tiossemicarbazonas/farmacologia , Testes de Sensibilidade Microbiana
8.
Microorganisms ; 10(1)2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-35056552

RESUMO

BACKGROUND: Sterols are the main components of fungal membranes. Inhibiting their biosynthesis is the mode of action of azole antifungal drugs that are widely used to treat fungal disease including aspergillosis. Azole resistance has emerged as a matter of concern but little is known about sterols biosynthesis in azole resistant Aspergillus fumigatus. METHODS: We explored the sterol composition of 12 A. fumigatus isolates, including nine azole resistant isolates with TR34/L98H, TR46/Y121F/T289A or TR53 alterations in the cyp51A gene and its promoter conferring azole resistance. Modifications in sterol composition were also investigated after exposure to two azole drugs, itraconazole and voriconazole. RESULTS: Overall, under basal conditions, sterol compositions were qualitatively equivalent, whatever the alterations in the target of azole drugs with ergosterol as the main sterol detected. Azole exposure reduced ergosterol composition and the qualitative composition of sterols was similar in both susceptible and resistant isolates. Interestingly TR53 strains behaved differently than other strains. CONCLUSIONS: Elucidating sterol composition in azole-susceptible and resistant isolates is of interest for a better understanding of the mechanism of action of these drugs and the mechanism of resistance of fungi.

9.
Eur J Med Chem ; 210: 112956, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33148491

RESUMO

Leishmaniasis constitutes a severe public health problem, with an estimated prevalence of 12 million cases. This potentially fatal disease has a worldwide distribution and in 2012, the fatal Visceral Leishmaniasis (VL) was declared as new emerging disease in Europe, mainly due to global warming, with expected important public health impact. The available treatments are toxic, costly or lead to parasite resistance, thus there is an urgent need for new drugs with new mechanism of action. Previously, we reported the discovery of CTN1122, a potent imidazo[1,2-a]pyrazine-based antileishmanial hit compound targeting L-CK1.2 at low micromolar ranges. Here, we described structurally related, safe and selective compounds endowed with antiparasitic properties, better than miltefosine, the reference therapy by oral route. L-CK1.2 homology model gave the first structural explanations of the role of 4-pyridyl (CTN1122) and 2-aminopyrimidin-4-yl (compound 21) moieties, at the position 3 of the central core, in the low micromolar to nanomolar L-CK1.2 inhibition, whereas N-methylpyrazole derivative 11 remained inactive against the parasite kinase.


Assuntos
Caseína Quinase I/antagonistas & inibidores , Imidazóis/farmacologia , Leishmania major/enzimologia , Pirazinas/farmacologia , Tripanossomicidas/farmacologia , Caseína Quinase I/metabolismo , Humanos , Imidazóis/química , Leishmania major/efeitos dos fármacos , Leishmania major/metabolismo , Leishmaniose/tratamento farmacológico , Leishmaniose/parasitologia , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/química , Tripanossomicidas/química
10.
J Biol Inorg Chem ; 15(5): 641-54, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20191372

RESUMO

Telomeres, the nucleoprotein complexes located at the ends of chromosomes, are involved in chromosome protection and genome stability. Telomeric repeat binding factor 1 (TRF1) and telomeric repeat binding factor 2 (TRF2) are the two telomeric proteins that bind to duplex telomeric DNA through interactions between their C-terminal domain and several guanines of the telomeric tract. Since the antitumour drug cisplatin binds preferentially to two adjacent guanines, we have investigated whether cisplatin adducts could affect the binding of TRF1 and TRF2 to telomeric DNA and the property of TRF2 to stimulate telomeric invasion, a process that is thought to participate in the formation of the t-loop. We show that the binding of TRF1 and TRF2 to telomeric sequences selectively modified by one GG chelate of cisplatin is markedly affected by cisplatin but that the effect is more drastic for TRF2 than for TRF1 (3-5-fold more sensitivity for TRF2 than for TRF1). We also report that platinum adducts cause a decrease in TRF2-dependent stimulation of telomeric invasion in vitro. Finally, in accordance with in vitro data, analysis of telomeric composition after cisplatin treatment reveals that 60% of TRF2 dissociate from telomeres.


Assuntos
Cisplatino/química , Cisplatino/farmacologia , DNA/química , DNA/metabolismo , Proteínas de Ligação a Telômeros/metabolismo , Telômero/química , Proteína 2 de Ligação a Repetições Teloméricas/metabolismo , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular , DNA/síntese química , Humanos , Ligação Proteica/efeitos dos fármacos , Complexo Shelterina , Telômero/metabolismo
11.
Eur J Med Chem ; 189: 112082, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32000050

RESUMO

We identified a new series of azole antifungal agents bearing a pyrrolotriazinone scaffold. These compounds exhibited a broad in vitro antifungal activity against pathogenic Candida spp. (fluconazole-susceptible and fluconazole-resistant) and were 10- to 100-fold more active than voriconazole against two Candida albicans isolates with known mechanisms of azole resistance (overexpression of efflux pumps and/or specific point substitutions in the Erg11p/CYP51 enzyme). Our lead compound 12 also displayed promising in vitro antifungal activity against some filamentous fungi such as Aspergillus fumigatus and the zygomycetes Rhizopus oryzae and Mucor circinelloides and an in vivo efficiency against two murine models of lethal systemic infections caused by Candida albicans.


Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Triazinas/química , Animais , Antifúngicos/química , Candidíase/microbiologia , Farmacorresistência Fúngica , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
12.
Pharmaceuticals (Basel) ; 12(4)2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842280

RESUMO

In this review, we discuss novel natural products discovered within the last decade that are reported to have antifungal activity against pathogenic species. Nearly a hundred natural products were identified that originate from bacteria, algae, fungi, sponges, and plants. Fungi were the most prolific source of antifungal compounds discovered during the period of review. The structural diversity of these antifungal leads encompasses all the major classes of natural products including polyketides, shikimate metabolites, terpenoids, alkaloids, and peptides.

13.
J Inorg Biochem ; 101(3): 514-24, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17224184

RESUMO

G-quadruplex structures of telomeric sequences are of growing interest because they inhibit telomerase, an enzyme involved in the maintenance of telomere length of cancer cells. As we have shown previously, the antiparallel structure of G-quadruplexes can be cross-linked in vitro by the anti-tumour drug cisplatin. The question arises whether platination of quadruplex structures of human telomeric sequences by cisplatin could be relevant from a biological point of view. Therefore, we have compared the kinetics of reactions of the diaqua form of cisplatin, cis-[Pt(NH(3))(2)(H(2)O)(2)](2+), with the human telomeric quadruplex structure, a duplex DNA and a single-stranded DNA containing one specific platination GG site. The ratio between the platination rate constants was obtained using two intramolecular competition experiments: either a construct with a junction between duplex DNA containing a unique GG platination site and the quadruplex structure of the human telomeric sequence AG(3)(T(2)AG(3))(3), or a construct with a junction between duplex DNA and a single strand containing each a unique GG platination site. Those competition experiments allowed us to conclude that the platination of the quadruplex is favoured over that of the GG duplex by a factor of about two whereas the GG duplex is platinated three times faster than the GG single strand.


Assuntos
Cisplatino/química , Adutos de DNA/química , Guanina/química , Telômero/química , Antineoplásicos/química , Reagentes de Ligações Cruzadas/química , DNA/química , DNA de Cadeia Simples/química , Eletroforese em Gel de Poliacrilamida , Quadruplex G , Humanos , Cinética , Modelos Moleculares , Dados de Sequência Molecular , Oligonucleotídeos/química , Compostos de Platina/química
14.
Methods Mol Biol ; 1587: 29-39, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28324495

RESUMO

Length is a functional parameter of telomeres, the nucleoprotein structures that protect chromosome ends. The availability of highly specific, high affinity probes for telomeric repeat sequences allowed the development of quantitative approaches aimed at measuring telomere length directly on chromosomes or in interphase nuclei. Here, we describe a general method for telomere quantitative FISH on metaphase chromosomes and discuss its most common applications in research.


Assuntos
Telômero/genética , Cromossomos/genética , Humanos , Hibridização in Situ Fluorescente/métodos , Interfase/genética , Metáfase/genética , Sequências Repetitivas de Ácido Nucleico/genética
15.
Methods Mol Biol ; 1587: 41-54, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28324496

RESUMO

The implementation of quantitative approaches in telomere chromosome-oriented FISH (telomeric CO-FISH) allows the assessment of the relative efficiency of lagging versus leading strand telomere replication and thus provides information on the implicated mechanisms. Here we describe a simple method for telomere strand-specific analyses and discuss its potential applications.


Assuntos
Telômero/genética , Cromossomos/genética , Humanos , Hibridização in Situ Fluorescente/métodos
16.
Methods Mol Biol ; 735: 21-31, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21461808

RESUMO

Length is a functional parameter of telomeres, the nucleoprotein structures that protect chromosome ends. The availability of highly specific, high-affinity probes for telomeric repeated sequences allowed the development of quantitative approaches aimed at measuring telomere length directly on chromosomes or in interphase nuclei. Here, we describe a general method for telomere quantitative FISH on metaphase chromosomes and discuss its most common applications in research.


Assuntos
Hibridização in Situ Fluorescente/métodos , Telômero/química , Células Cultivadas , Cromossomos/química , Humanos , Telômero/metabolismo
17.
Methods Mol Biol ; 735: 33-46, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21461809

RESUMO

The implementation of quantitative approaches in telomere chromosome-oriented FISH (telomeric CO-FISH) allows the assessment of the relative efficiency of lagging versus leading strand telomere replication and thus provides information on the implicated mechanisms. Here, we describe a simple method for telomere strand-specific analyses and discuss its potential applications.


Assuntos
Hibridização in Situ Fluorescente/métodos , Telômero/química , Células Cultivadas , Replicação do DNA , Humanos , Telômero/metabolismo
18.
PLoS One ; 5(12): e14249, 2010 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-21170331

RESUMO

BACKGROUND: Gene amplification is thought to promote over-expression of genes favouring tumour development. Because amplified regions are usually megabase-long, amplification often concerns numerous syntenic or non-syntenic genes, among which only a subset is over-expressed. The rationale for these differences remains poorly understood. METHODOLOGY/PRINCIPAL FINDING: To address this question, we used quantitative RT-PCR to determine the expression level of a series of co-amplified genes in five xenografted and one fresh human gliomas. These gliomas were chosen because we have previously characterised in detail the genetic content of their amplicons. In all the cases, the amplified sequences lie on extra-chromosomal DNA molecules, as commonly observed in gliomas. We show here that genes transcribed in non-amplified gliomas are over-expressed when amplified, roughly in proportion to their copy number, while non-expressed genes remain inactive. When specific antibodies were available, we also compared protein expression in amplified and non-amplified tumours. We found that protein accumulation barely correlates with the level of mRNA expression in some of these tumours. CONCLUSIONS/SIGNIFICANCE: Here we show that the tissue-specific pattern of gene expression is maintained upon amplification in gliomas. Our study relies on a single type of tumour and a limited number of cases. However, it strongly suggests that, even when amplified, genes that are normally silent in a given cell type play no role in tumour progression. The loose relationships between mRNA level and protein accumulation and/or activity indicate that translational or post-translational events play a key role in fine-tuning the final outcome of amplification in gliomas.


Assuntos
Neoplasias Encefálicas/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioma/metabolismo , DNA/genética , Progressão da Doença , Receptores ErbB/metabolismo , Inativação Gênica , Glioblastoma/metabolismo , Humanos , Transplante de Neoplasias , Oligodendroglioma/metabolismo , Processamento de Proteína Pós-Traducional , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Telomerase/metabolismo
19.
Biochemistry ; 44(31): 10620-34, 2005 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-16060671

RESUMO

The folding of AG(3)(T(2)AG(3))(3) was investigated in the presence of Na(+) or K(+) ions, by using the dinuclear platinum complexes [{trans-PtCl(NH(3))(2)}(2)H(2)N(CH(2))(n)NH(2)]Cl(2) (n = 2 or 6). AG(3)(T(2)AG(3))(3) has been previously found to adopt two different quadruplex structures: the antiparallel one in a solution containing Na(+) and the parallel one in a K(+)-containing crystal. The two structures are strikingly distinct and are not expected to form the same platinum cross-links. Therefore, characterization of the cross-links formed with platinum complexes in solution allowed the predominant conformation(s) to be identified. The bases coordinating the platinum atoms were identified by chemical and 3'-exonuclease digestions. The observed cross-links showed that the parallel structure exists in solution whatever the cation and confirmed the existence of the antiparallel structure in the presence of both cations as previously reported from cross-linking experiments of AG(3)(T(2)AG(3))(3) by mononuclear platinum complexes. Furthermore, the major platinum cross-links were unexpectedly formed between two guanines belonging to the same G-quartet. Their formation was rationalized using molecular dynamics simulations in implicit solvent of the two quadruplex structures. It was shown that they were flexible, allowing some guanines to leave reversibly the top G-quartet and thus rendering their N(7) atom accessible to platinum complexes. Our results also suggest that the human telomere sequence could be a target for such platinum complexes.


Assuntos
Reagentes de Ligações Cruzadas/química , DNA/química , Compostos Organoplatínicos/química , Telômero/química , Termodinâmica , Sítios de Ligação , Cátions Monovalentes , Simulação por Computador , Reagentes de Ligações Cruzadas/metabolismo , DNA/metabolismo , Adutos de DNA/química , Adutos de DNA/metabolismo , Quadruplex G , Guanina/química , Humanos , Modelos Moleculares , Compostos Organoplatínicos/metabolismo , Potássio , Sódio , Soluções , Solventes , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Ésteres do Ácido Sulfúrico/química , Telômero/metabolismo
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