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1.
PLoS Biol ; 18(4): e3000655, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32240158

RESUMO

Recent advances in animal tracking technology have ushered in a new era in biologging. However, the considerable size of many sophisticated biologging devices restricts their application to larger animals, whereas older techniques often still represent the state-of-the-art for studying small vertebrates. In industrial applications, low-power wireless sensor networks (WSNs) fulfill requirements similar to those needed to monitor animal behavior at high resolution and at low tag mass. We developed a wireless biologging network (WBN), which enables simultaneous direct proximity sensing, high-resolution tracking, and long-range remote data download at tag masses of 1 to 2 g. Deployments to study wild bats created social networks and flight trajectories of unprecedented quality. Our developments highlight the vast capabilities of WBNs and their potential to close an important gap in biologging: fully automated tracking and proximity sensing of small animals, even in closed habitats, at high spatial and temporal resolution.


Assuntos
Quirópteros , Monitoramento Ambiental/métodos , Tecnologia de Sensoriamento Remoto/métodos , Tecnologia sem Fio , Animais , Comportamento Animal , Quirópteros/fisiologia , Ecossistema , Fontes de Energia Elétrica , Monitoramento Ambiental/instrumentação , Feminino , Alemanha , Masculino , Panamá , Comportamento Social , Análise Espaço-Temporal , Clima Tropical , Vertebrados
2.
BMC Med ; 20(1): 35, 2022 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-35081949

RESUMO

BACKGROUND: The development of the human placenta is tightly coordinated by a multitude of placental cell types, including human chorionic villi mesenchymal stromal cells (hCV-MSCs). Defective hCV-MSCs have been reported in preeclampsia (PE), a gestational hypertensive disease characterized by maternal endothelial dysfunction and systemic inflammation. Our goal was to determine whether hCV-MSCs are ciliated and whether altered ciliation is responsible for defective hCV-MSCs in preeclamptic placentas, as the primary cilium is a hub for signal transduction, which is important for various cellular activities. METHODS: In the present work, we collected placental tissues from different gestational stages and we isolated hCV-MSCs from 1st trimester, term control, and preeclamptic placentas. We studied their ciliation, functionality, and impact on trophoblastic cell lines and organoids formed from human trophoblast stem cells (hTSCs) and from the trophoblastic cell line JEG-3 with various cellular and molecular methods, including immunofluorescence staining, gene analysis, spheroid/organoid formation, motility, and cellular network formation assay. The statistical evaluation was performed using a Student's t test (two-tailed and paired or homoscedastic) or an unpaired Mann-Whitney U test (two-tailed). RESULTS: The results show that primary cilia appeared abundantly in normal hCV-MSCs, especially in the early development of the placenta. Compared to control hCV-MSCs, the primary cilia were truncated, and there were fewer ciliated hCV-MSCs derived from preeclamptic placentas with impaired hedgehog signaling. Primary cilia are necessary for hCV-MSCs' proper signal transduction, motility, homing, and differentiation, which are impaired in preeclamptic hCV-MSCs. Moreover, hCV-MSCs derived from preeclamptic placentas are significantly less capable of promoting growth and differentiation of placental organoids, as well as cellular network formation. CONCLUSIONS: These data suggest that the primary cilium is required for the functionality of hCV-MSCs and primary cilia are impaired in hCV-MSCs from preeclamptic placentas.


Assuntos
Células-Tronco Mesenquimais , Pré-Eclâmpsia , Linhagem Celular Tumoral , Feminino , Proteínas Hedgehog/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismo , Placenta/metabolismo , Gravidez
3.
Sensors (Basel) ; 18(10)2018 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-30301239

RESUMO

In this paper, the BATS project is presented, which aims to track the behavior of bats via an ultra-low power wireless sensor network. An overview about the whole project and its parts like sensor node design, tracking grid and software infrastructure is given and the evaluation of the project is shown. The BATS project includes a lightweight sensor node that is attached to bats and combines multiple features. Communication among sensor nodes allows tracking of bat encounters. Flight trajectories of individual tagged bats can be recorded at high spatial and temporal resolution by a ground node grid. To increase the communication range, the BATS project implemented a long-range telemetry system to still receive sensor data outside the standard ground node network. The whole system is designed with the common goal of ultra-low energy consumption while still maintaining optimal measurement results. To this end, the system is designed in a flexible way and is able to adapt its functionality according to the current situation. In this way, it uses the energy available on the sensor node as efficient as possible.


Assuntos
Tecnologia sem Fio , Algoritmos , Animais , Redes de Comunicação de Computadores , Software , Telemetria
4.
Bioorg Med Chem Lett ; 22(12): 3873-8, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22608962

RESUMO

A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.


Assuntos
Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Hipoglicemiantes/síntese química , Oxidiazóis/síntese química , Animais , Diabetes Mellitus/tratamento farmacológico , Diacilglicerol O-Aciltransferase/metabolismo , Cães , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Meia-Vida , Ensaios de Triagem em Larga Escala , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Ligantes , Camundongos , Obesidade/tratamento farmacológico , Oxidiazóis/farmacocinética , Relação Quantitativa Estrutura-Atividade , Ratos
6.
Cells ; 10(9)2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34571867

RESUMO

Preeclampsia (PE), a gestational hypertensive disease originating from the placenta, is characterized by an imbalance of various cellular processes. The cell cycle regulator p21Cip1/CDKN1A (p21) and its family members p27 and p57 regulate signaling pathways fundamental to placental development. The aim of the present study was to enlighten the individual roles of these cell cycle regulators in placental development and their molecular involvement in the pathogenesis of PE. The expression and localization of p21, phospho-p21 (Thr-145), p27, and p57 was immunohistochemically analyzed in placental tissues from patients with early-onset PE, early-onset PE complicated by the HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome as well as late-onset PE compared to their corresponding control tissues from well-matched women undergoing caesarean sections. The gene level was evaluated using real-time quantitative PCR. We demonstrate that the delivery mode strongly influenced placental gene expression, especially for CDKN1A (p21) and CDKN1B (p27), which were significantly upregulated in response to labor. Cell cycle regulators were highly expressed in first trimester placentas and impacted by hypoxic conditions. In support of these observations, p21 protein was abundant in trophoblast organoids and hypoxia reduced its gene expression. Microarray analysis of the trophoblastic BeWo cell line depleted of p21 revealed various interesting candidate genes and signaling pathways for the fusion process. The level of p21 was reduced in fusing cytotrophoblasts in early-onset PE placentas and depletion of p21 led to reduced expression of fusion-related genes such as syncytin-2 and human chorionic gonadotropin (ß-hCG), which adversely affected the fusion capability of trophoblastic cells. These data highlight that cell cycle regulators are important for the development of the placenta. Interfering with p21 influences multiple pathways related to the pathogenesis of PE.


Assuntos
Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Trofoblastos/metabolismo , Adulto , Gonadotropina Coriônica/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Feminino , Expressão Gênica/fisiologia , Humanos , Placentação/fisiologia , Gravidez , Primeiro Trimestre da Gravidez/metabolismo
7.
ACS Chem Biol ; 12(12): 3113-3125, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29131570

RESUMO

The ubiquitin proteasome system is widely postulated to be a new and important field of drug discovery for the future, with the ubiquitin specific proteases (USPs) representing one of the more attractive target classes within the area. Many USPs have been linked to critical axes for therapeutic intervention, and the finding that USP28 is required for c-Myc stability suggests that USP28 inhibition may represent a novel approach to targeting this so far undruggable oncogene. Here, we describe the discovery of the first reported inhibitors of USP28, which we demonstrate are able to bind to and inhibit USP28, and while displaying a dual activity against the closest homologue USP25, these inhibitors show a high degree of selectivity over other deubiquitinases (DUBs). The utility of these compounds as valuable probes to investigate and further explore cellular DUB biology is highlighted by the demonstration of target engagement against both USP25 and USP28 in cells. Furthermore, we demonstrate that these inhibitors are able to elicit modulation of both the total levels and the half-life of the c-Myc oncoprotein in cells and also induce apoptosis and loss of cell viability in a range of cancer cell lines. We however observed a narrow therapeutic index compared to a panel of tissue-matched normal cell lines. Thus, it is hoped that these probes and data presented herein will further advance our understanding of the biology and tractability of DUBs as potential future therapeutic targets.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Ubiquitina Tiolesterase/antagonistas & inibidores , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/química , Células HCT116 , Humanos
8.
J Med Chem ; 59(13): 6281-92, 2016 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-27259031

RESUMO

A novel series of 3-quinoline carboxamides has been discovered and optimized as selective inhibitors of the ataxia telangiectasia mutated (ATM) kinase. From a modestly potent HTS hit (4), we identified molecules such as 6-[6-(methoxymethyl)-3-pyridinyl]-4-{[(1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl]amino}-3-quinolinecarboxamide (72) and 7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(1S)-1-(1-methyl-1H-pyrazol-3-yl)ethyl]amino}quinoline-3-carboxamide (74) as potent and highly selective ATM inhibitors with overall ADME properties suitable for oral administration. 72 and 74 constitute excellent oral tools to probe ATM inhibition in vivo. Efficacy in combination with the DSB-inducing agent irinotecan was observed in a disease relevant model.


Assuntos
Antineoplásicos/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Quinolinas/administração & dosagem , Quinolinas/química , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Med Chem ; 58(5): 2265-74, 2015 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-25695162

RESUMO

Constitutively active mutant KRas displays a reduced rate of GTP hydrolysis via both intrinsic and GTPase-activating protein-catalyzed mechanisms, resulting in the perpetual activation of Ras pathways. We describe a fragment screening campaign using X-ray crystallography that led to the discovery of three fragment binding sites on the Ras:SOS complex. The identification of tool compounds binding at each of these sites allowed exploration of two new approaches to Ras pathway inhibition by stabilizing or covalently modifying the Ras:SOS complex to prevent the reloading of Ras with GTP. Initially, we identified ligands that bound reversibly to the Ras:SOS complex in two distinct sites, but these compounds were not sufficiently potent inhibitors to validate our stabilization hypothesis. We conclude by demonstrating that covalent modification of Cys118 on Ras leads to a novel mechanism of inhibition of the SOS-mediated interaction between Ras and Raf and is effective at inhibiting the exchange of labeled GDP in both mutant (G12C and G12V) and wild type Ras.


Assuntos
Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteína SOS1/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Humanos , Modelos Moleculares , Estrutura Molecular , Mutação/genética , Ligação Proteica/efeitos dos fármacos , Conformação Proteica , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína SOS1/química , Bibliotecas de Moléculas Pequenas/química
10.
Drug Discov Today ; 18(5-6): 298-304, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23117010

RESUMO

Clinically useful drugs target a relatively small number of proteins that lie within a clearly defined and chemically accessible space. However, many high value biological targets lie outside this chemical space, and an ability to access such 'intractable' targets not amenable to traditional small molecule intervention would expand treatment options and be a major boost for patients and the pharmaceutical industry. To date, success has been limited but new technologies and approaches are beginning to emerge that could provide novel lead generation capabilities that enable access to new drug target classes. We review these new approaches and their ability to provide the novel leads needed to tackle a new generation of biological targets.


Assuntos
Química Farmacêutica , Produtos Biológicos , Sistemas de Liberação de Medicamentos , Ensaios de Triagem em Larga Escala , Bibliotecas de Moléculas Pequenas , Biologia de Sistemas
12.
Cell Biochem Biophys ; 60(1-2): 99-111, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21468692

RESUMO

USP7 (HAUSP) is a deubiquitinating enzyme, which plays a crucial role in regulating the levels of the p53 tumour suppressor protein, through its ability to prevent the proteasomal degradation of the Ubiquitin ligase for p53, Hdm2. Supporting evidence suggests that an inhibitor of USP7 would act to abrogate the action of Hdm2, and thereby elevate levels of the p53 protein, with associated therapeutic benefits in cancer and potentially other diseases. In this article, we describe the characterisation of differential enzyme activity of both the full length and putative catalytic domain of human USP7 expressed in both bacterial and insect cell expression systems. We also demonstrate the way in which variations in the reducing environment surrounding the enzyme can dramatically affect both the stability of the enzyme and the range of small molecules able to inhibit the catalytic activity of the enzyme. Furthermore, we describe the validation and use of this assay for a high-throughput screening approach, again highlighting the critical nature of the enzyme's environment. Taken together, these findings not only increase our understanding of the enzymatic activity of deubiquitinating enzymes, but also highlight several key considerations of importance in the development of therapeutic agents against this novel class of therapeutic targets.


Assuntos
Inibidores Enzimáticos/farmacologia , Ubiquitina Tiolesterase/antagonistas & inibidores , Ubiquitina Tiolesterase/metabolismo , Ubiquitina/metabolismo , Sequência de Aminoácidos , Animais , Biocatálise/efeitos dos fármacos , Domínio Catalítico/genética , Linhagem Celular , Cumarínicos/metabolismo , Ditiotreitol/farmacologia , Relação Dose-Resposta a Droga , Eletroforese em Gel de Poliacrilamida , Estabilidade Enzimática , Glutationa/farmacologia , Humanos , Cinética , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Maleimidas/farmacologia , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Espectrometria de Fluorescência , Spodoptera , Especificidade por Substrato , Temperatura , Ubiquitina/genética , Ubiquitina Tiolesterase/genética , Peptidase 7 Específica de Ubiquitina , Ubiquitinas/metabolismo
14.
Curr Top Med Chem ; 7(16): 1600-29, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17979771

RESUMO

Fragment-based lead generation (FBLG) has recently emerged as an alternative to traditional high throughput screening (HTS) to identify initial chemistry starting points for drug discovery programs. In comparison to HTS screening libraries, the screening sets for FBLG tend to contain orders of magnitude fewer compounds, and the compounds themselves are less structurally complex and have lower molecular weight. This report summarises the advent of FBLG within the industry and then describes the FBLG experience at AstraZeneca. We discuss (1) optimising the design of screening libraries, (2) hit detection methodologies, (3) evaluation of hit quality and use of ligand efficiency calculations, and (4) approaches to evolve fragment-based, low complexity hits towards drug-like leads. Furthermore, we exemplify our use of FBLG with case studies in the following drug discovery areas: antibacterial enzyme targets, GPCRs (melanocortin 4 receptor modulators), prostaglandin D2 synthase inhibitors, phosphatase inhibitors (protein tyrosine phosphotase 1B), and protease inhibitors (b-secretase).


Assuntos
Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Proteínas/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas , Técnicas de Química Combinatória , Indústria Farmacêutica/métodos , Inibidores Enzimáticos , Ligantes , Ligação Proteica
15.
J Virol ; 80(13): 6691-6, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16775357

RESUMO

Papillomaviruses enter cells via endocytosis (H. C. Selinka et al., Virology 299:279-287, 2002). After egress from endosomes, the minor capsid protein L2 accompanies the viral DNA to the nucleus and subsequently to the subnuclear promyelocytic leukemia protein bodies (P. M. Day et al., Proc. Natl. Acad. Sci. USA 101:14252-14257, 2004), suggesting that this protein may be involved in the intracytoplasmic transport of the viral genome. We now demonstrate that the L2 protein is able to interact with the microtubule network via the motor protein dynein. L2 protein was found attached to microtubules after uncoating of incoming human papillomavirus pseudovirions. Based on immunofluorescence and coimmunoprecipitation analyses, the L2 region interacting with dynein is mapped to the C-terminal 40 amino acids. Mutations within this region abrogating the L2/dynein interaction strongly reduce the infectivity of pseudoviruses, indicating that this interaction mediates the minus-end-directed transport of the viral genome along microtubules towards the nucleus.


Assuntos
Proteínas do Capsídeo/metabolismo , DNA Viral/metabolismo , Dineínas/metabolismo , Espaço Intranuclear/metabolismo , Proteínas Oncogênicas Virais/metabolismo , Transporte Ativo do Núcleo Celular/genética , Proteínas do Capsídeo/genética , Endocitose/genética , Genoma Viral/genética , Células HeLa , Humanos , Espaço Intranuclear/virologia , Microscopia de Fluorescência , Microtúbulos/metabolismo , Microtúbulos/virologia , Proteínas Oncogênicas Virais/genética , Papillomaviridae/metabolismo , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/metabolismo , Ligação Proteica
16.
J Virol ; 80(2): 759-68, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16378978

RESUMO

Papillomaviruses are internalized via clathrin-dependent endocytosis. However, the mechanism by which viral genomes pass endosomal membranes has not been elucidated. In this report we show that the minor capsid protein L2 is required for egress of viral genomes from endosomes but not for initial uptake and uncoating and that a 23-amino-acid peptide at the C terminus of L2 is necessary for this function. Pseudogenomes encapsidated by L1 and L2 lacking this peptide accumulated in vesicular compartments similar to that observed with L1-only viral particles, and these mutant pseudoviruses were noninfectious. This L2 peptide displayed strong membrane-disrupting activity, induced cytolysis of bacteria and eukaryotic cells in a pH-dependent manner, and permeabilized cells after exogenous addition. Fusions between green fluorescent protein and the L2 peptide integrated into cellular membranes like the wild type but not like C-terminal mutants of L2. Our data indicate that the L2 C terminus facilitates escape of viral genomes from the endocytic compartment and that this feature is conserved among papillomaviruses. Furthermore, the characteristic of this peptide differs from the classical virus-encoded membrane-penetrating peptides.


Assuntos
Proteínas do Capsídeo/genética , Papillomaviridae/fisiologia , Sequência de Aminoácidos , Animais , Linhagem Celular , Endossomos/virologia , Genoma Viral , Humanos , Dados de Sequência Molecular , Mutação , Infecções por Papillomavirus/virologia , Replicação Viral
17.
J Virol ; 77(24): 12961-7, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14645552

RESUMO

Cell surface heparan sulfate proteoglycans (HSPGs) serve as primary attachment receptors for human papillomaviruses (HPVs). To demonstrate that a biologically functional HPV-receptor interaction is restricted to a specific subset of HSPGs, we first explored the role of HSPG glucosaminoglycan side chain modifications. We demonstrate that HSPG O sulfation is essential for HPV binding and infection, whereas de-N-sulfated heparin interfered with VLP binding but not with HPV pseudoinfection. This points to differences in VLP-HSPG and pseudovirion-HSPG interactions. Interestingly, internalization kinetics of VLPs and pseudovirions, as measured by fluorescence-activated cell sorting analysis, also differ significantly with approximate half times of 3.5 and 7.5 h, respectively. These data suggest that differences in HSPG binding significantly influence postbinding events. We also present evidence that pseudovirions undergo a conformational change after cell attachment. A monoclonal antibody (H33.J3), which displays negligible effectiveness in preattachment neutralization assays, efficiently neutralizes cell-bound virions. However, no difference in H33.J3 binding to pseudovirions and VLPs was observed in enzyme-linked immunosorbent assay and virus capture assays. In contrast to antibody H33.B6, which displays equal efficiencies in pre- and postattachment neutralization assays, H33.J3 does not block VLP binding to heparin, demonstrating that it interferes with steps subsequent to virus binding. Our data strongly suggest that H33.J3 recognizes a conformation-dependent epitope in capsid protein L1, which undergoes a structural change after cell attachment.


Assuntos
Capsídeo/química , Capsídeo/metabolismo , Proteoglicanas de Heparan Sulfato/metabolismo , Papillomaviridae/patogenicidade , Conformação Proteica , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/metabolismo , Células COS , Proteínas do Capsídeo/química , Proteínas do Capsídeo/imunologia , Proteínas do Capsídeo/metabolismo , Chlorocebus aethiops , Epitopos/imunologia , Citometria de Fluxo , Humanos , Camundongos , Testes de Neutralização , Papillomaviridae/fisiologia , Receptores Virais/metabolismo , Vírion/metabolismo , Vírion/fisiologia
18.
Bioorg Med Chem ; 11(12): 2617-26, 2003 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-12757727

RESUMO

A library of 51 analogues of the naturally occurring protein farnesyltransferase inhibitor pepticinnamin E was investigated biologically. Several compounds with pronounced inhibitory activity were discovered with the lowest IC(50) value reaching 1 microM. The library contains inhibitors which are competitive to either farnesylpyrophosphate or the peptide substrate and a bisubstrate inhibitor. This activity is supported and rationalized by molecular modelling experiments and different binding modes of the inhibitors deduced from them. Several compounds induced apoptosis in a Ras-transformed tumour cell line, and in one case this correlated with farnesyltransferase-inhibiting activity.


Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Cães , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase , Humanos , Modelos Moleculares , Biblioteca de Peptídeos , Ratos , Relação Estrutura-Atividade , Especificidade por Substrato , Proteínas ras/metabolismo
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