RESUMEN
Hypoxia inducible factor (HIF) is a heterodimeric transcription factor composed of an oxygen-regulated α subunit and a constitutively expressed ß subunit that serves as the master regulator of the cellular response to low oxygen concentrations. The HIF transcription factor senses and responds to hypoxia by significantly altering transcription and reprogramming cells to enable adaptation to a hypoxic microenvironment. Given the central role played by HIF in the survival and growth of tumors in hypoxia, inhibition of this transcription factor serves as a potential therapeutic approach for treating a variety of cancers. Here, we report the identification, optimization, and characterization of a series of cyclic peptides that disrupt the function of HIF-1 and HIF-2 transcription factors by inhibiting the interaction of both HIF-1α and HIF-2α with HIF-1ß. These compounds are shown to bind to HIF-α and disrupt the protein-protein interaction between the α and ß subunits of the transcription factor, resulting in disruption of hypoxia-response signaling by our lead molecule in several cancer cell lines.
Asunto(s)
Factor 1 Inducible por Hipoxia , Neoplasias , Humanos , Factor 1 Inducible por Hipoxia/metabolismo , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/metabolismo , Hipoxia , Transducción de Señal , Oxígeno/metabolismo , Hipoxia de la Célula , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias/tratamiento farmacológicoRESUMEN
Inspired by interlocked oligonucleotides, peptides and knotted proteins, synthetic systems where a macrocycle cages a bioactive species that is "switched on" by breaking the mechanical bond have been reported. However, to date, each example uses a bespoke chemical design. Here we present a platform approach to mechanically caged structures wherein a single macrocycle precursor is diversified at a late stage to include a range of trigger units that control ring opening in response to enzymatic, chemical, or photochemical stimuli. We also demonstrate that our approach is applicable to other classes of macrocycles suitable for rotaxane and catenane formation.
RESUMEN
The purinosome is a dynamic metabolic complex composed of enzymes responsible for de novo purine biosynthesis, whose formation has been associated with elevated purine demand. However, the physiological conditions that govern purinosome formation in cells remain unknown. Here, we report that purinosome formation is up-regulated in cells in response to a low-oxygen microenvironment (hypoxia). We demonstrate that increased purinosome assembly in hypoxic human cells requires the activation of hypoxia inducible factor 1 (HIF-1) and not HIF-2. Hypoxia-driven purinosome assembly was inhibited in cells lacking 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), a single enzyme in de novo purine biosynthesis, and in cells treated with a small molecule inhibitor of ATIC homodimerization. However, despite the increase in purinosome assembly in hypoxia, we observed no associated increase in de novo purine biosynthesis in cells. Our results indicate that this was likely due to a reduction in mitochondrial one-carbon metabolism, resulting in reduced mitochondrion-derived one-carbon units needed for de novo purine biosynthesis. The findings of our study further clarify and deepen our understanding of purinosome formation by revealing that this process does not solely depend on cellular purine demand.
Asunto(s)
Transferasas de Hidroximetilo y Formilo/metabolismo , Factor 1 Inducible por Hipoxia/metabolismo , Complejos Multienzimáticos/metabolismo , Nucleótido Desaminasas/metabolismo , Purinas/biosíntesis , Hipoxia de la Célula , Células HeLa , Humanos , Transferasas de Hidroximetilo y Formilo/genética , Factor 1 Inducible por Hipoxia/genética , Complejos Multienzimáticos/genética , Nucleótido Desaminasas/genéticaRESUMEN
We present a simple strategy for the synthesis of main chain oligonucleotide rotaxanes with precise control over the position of the macrocycle. The novel DNA-based rotaxanes were analyzed to assess the effect of the mechanical bond on their properties.
Asunto(s)
Cobre/química , ADN/síntesis química , Oligonucleótidos/síntesis química , Rotaxanos/síntesis química , Alquinos/síntesis química , Alquinos/química , Azidas/síntesis química , Azidas/química , Química Clic , Reacción de Cicloadición , ADN/química , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/química , Oligonucleótidos/química , Rotaxanos/químicaRESUMEN
In this article we describe the production and screening of a genetically encoded library of 106 lanthipeptides in Escherichia coli using the substrate-tolerant lanthipeptide synthetase ProcM. This plasmid-encoded library was combined with a bacterial reverse two-hybrid system for the interaction of the HIV p6 protein with the UEV domain of the human TSG101 protein, which is a critical protein-protein interaction for HIV budding from infected cells. Using this approach, we identified an inhibitor of this interaction from the lanthipeptide library, whose activity was verified in vitro and in cell-based virus-like particle-budding assays. Given the variety of lanthipeptide backbone scaffolds that may be produced with ProcM, this method may be used for the generation of genetically encoded libraries of natural product-like lanthipeptides containing substantial structural diversity. Such libraries may be combined with any cell-based assay to identify lanthipeptides with new biological activities.
Asunto(s)
Proteínas de Unión al ADN/química , Complejos de Clasificación Endosomal Requeridos para el Transporte/química , Escherichia coli/metabolismo , Péptido Sintasas/química , Péptidos/química , Factores de Transcripción/química , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/química , Cristalografía por Rayos X , Receptores ErbB/metabolismo , Proteínas de Escherichia coli/química , Etilmaleimida/química , Biblioteca de Genes , Células HEK293 , VIH , Células HeLa , Humanos , Concentración 50 Inhibidora , Yodoacetamida/química , Péptido Hidrolasas/química , Plásmidos , Dominios Proteicos , Mapeo de Interacción de Proteínas , Especificidad por SustratoRESUMEN
We report an inhibitor of the homodimeric protein-protein interaction of the BCL6 oncoprotein, identified from a genetically encoded SICLOPPS library of 3.2 million cyclic hexapeptides in combination with a bacterial reverse two-hybrid system. This cyclic peptide is shown to bind the BTB domain of BCL6, disrupts its homodimerization, and subsequent binding of the SMRT2 corepressor peptide.
Asunto(s)
Biblioteca de Genes , Péptidos Cíclicos/farmacología , Proteínas Proto-Oncogénicas c-bcl-6/antagonistas & inhibidores , Dimerización , Estructura Molecular , Péptidos Cíclicos/química , Péptidos Cíclicos/genética , Unión Proteica , Proteínas Proto-Oncogénicas c-bcl-6/genéticaRESUMEN
A new class of anion transporter named 'perenosins' consisting of a pyrrole linked through an imine to either an indole, benzimidazole or indazole is reported. The indole containing members of the perenosin family function as effective transmembrane Cl(-)/NO3(-) antiporters and HCl cotransporters in a manner similar to the prodigiosenes. The compounds reduce the viability of MDA-MB-231 and MCF-7.
Asunto(s)
Aniones/metabolismo , Antineoplásicos Fitogénicos/farmacología , Antiportadores/farmacología , Iminas/química , Indoles/farmacología , Pirroles/farmacología , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Antiportadores/síntesis química , Antiportadores/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Indoles/química , Transporte Iónico/efectos de los fármacos , Células MCF-7 , Modelos Moleculares , Estructura Molecular , Pirroles/síntesis química , Pirroles/química , Relación Estructura-ActividadRESUMEN
The phage-shock protein (Psp) response is an extracytoplasmic response system that is vital for maintenance of the cytoplasmic membrane when the cell encounters stressful conditions. The paradigm of the Psp response has been established in Escherichia coli. The response has been shown to be important for survival during the stationary phase, maintenance of the proton motive force across membranes and implicated in virulence. In this study, we identified a putative PspA homologue in Burkholderia pseudomallei, annotated as BPSL2105. Similar to the induction of PspA in E. coli, the expression of B. pseudomallei BPSL2105 was induced by heat shock. Deletion of BPSL2105 resulted in a survival defect in the late stationary phase coincident with dramatic changes in the pH of the culture medium. The B. pseudomallei BPSL2105 deletion mutant also displayed reduced survival in macrophage infection - the first indication that the Psp response plays a role during intracellular pathogenesis in this species. The purified protein formed large oligomeric structures similar to those observed for the PspA protein of E. coli, and PspA homologues in Bacillus, cyanobacteria and higher plants, providing further evidence to support the identification of BPSL2105 as a PspA-like protein in B. pseudomallei.
Asunto(s)
Proteínas Bacterianas/metabolismo , Burkholderia pseudomallei/fisiología , Proteínas de Choque Térmico/metabolismo , Estrés Fisiológico , Burkholderia pseudomallei/genética , Burkholderia pseudomallei/efectos de la radiación , Medios de Cultivo/química , Eliminación de Gen , Perfilación de la Expresión Génica , Calor , Concentración de Iones de Hidrógeno , Macrófagos/inmunología , Macrófagos/microbiología , Viabilidad Microbiana/efectos de la radiación , Multimerización de ProteínaRESUMEN
Cyclic peptides are an emerging class of molecular therapeutics that are increasingly viewed as ideal backbones for modulation of protein-protein interactions. A split-intein based method, termed SICLOPPS, enables the rapid generation of genetically encoded cyclic peptide libraries of around a hundred million members. Here we review recent approaches using SICLOPPS for the discovery of bioactive compounds.
Asunto(s)
Péptidos Cíclicos/química , Descubrimiento de Drogas , Biblioteca de Péptidos , Péptidos Cíclicos/genética , Péptidos Cíclicos/metabolismo , Plásmidos/genética , Plásmidos/metabolismo , Dominios y Motivos de Interacción de Proteínas , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismoRESUMEN
Very high diastereoselectivity can be achieved by 1,3-chelation-controlled allylation of aldehydes that possess a non-chelating α-ether substituent, even if the α-position is a quaternary centre and/or a spiro-epoxide. This reaction was used as a key step in an enantioselective synthesis of the angiogenesis inhibitor luminacinâ D.
Asunto(s)
Aldehídos/química , Benzaldehídos/química , Quelantes/química , Compuestos Epoxi/química , Éter/química , Compuestos de Espiro/química , Catálisis , EstereoisomerismoRESUMEN
The biocompatibility of a triazole mimic of the DNA phosphodiester linkage in Escherichia coli has been evaluated. The requirement for selective pressure on the click-containing gene was probed via a plasmid containing click DNA backbone linkages in each strand of the gene encoding the fluorescent protein mCherry. The effect of proximity of the click linkers on their biocompatibility was also probed by placing two click DNA linkers 4-bp apart at the region encoding the fluorophore of the fluorescent protein. The resulting click-containing plasmid was found to encode mCherry in E. coli at a similar level to the canonical equivalent. The ability of the cellular machinery to read through click-linked DNA was further probed by using the above click-linked plasmid to express mCherry using an in vitro transcription/translation system, and found to also be similar to that from canonical DNA. The yield and fluorescence of recombinant mCherry expressed from the click-linked plasmid was also compared to that from the canonical equivalent, and found to be the same. The biocompatibility of click DNA ligation sites at close proximity in a non-essential gene demonstrated in E. coli suggests the possibility of using click DNA ligation for the enzyme-free assembly of chemically modified genes and genomes.
Asunto(s)
ADN/química , Escherichia coli/genética , Química Clic , Proteínas Luminiscentes/análisis , Proteínas Luminiscentes/genética , Mutagénesis Sitio-Dirigida , Plásmidos/genética , Triazoles/química , Proteína Fluorescente RojaRESUMEN
A triazole mimic of a DNA phosphodiester linkage has been produced by templated chemical ligation of oligonucleotides functionalized with 5'-azide and 3'-alkyne. The individual azide and alkyne oligonucleotides were synthesized by standard phosphoramidite methods and assembled using a straightforward ligation procedure. This highly efficient chemical equivalent of enzymatic DNA ligation has been used to assemble a 300-mer from three 100-mer oligonucleotides, demonstrating the total chemical synthesis of very long oligonucleotides. The base sequences of the DNA strands containing this artificial linkage were copied during PCR with high fidelity and a gene containing the triazole linker was functional in Escherichia coli.
Asunto(s)
ADN/síntesis química , Secuencia de Bases , ADN/química , ADN/genética , ADN Polimerasa Dirigida por ADN/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Imitación Molecular , Datos de Secuencia Molecular , Estructura Molecular , Oligodesoxirribonucleótidos/síntesis química , Oligodesoxirribonucleótidos/química , Oligodesoxirribonucleótidos/genética , Reacción en Cadena de la Polimerasa , Homología de Secuencia de Ácido Nucleico , Triazoles/químicaRESUMEN
Click DNA ligation promises an alternative to the current enzymatic approaches for DNA assembly, with the ultimate goal of using efficient chemical reactions for the total chemical synthesis and assembly of genes and genomes. Such an approach would enable the incorporation of various chemically modified bases throughout long stretches of DNA, a feat not possible with current polymerase-based methods. An unequivocal requirement for this approach is the biocompatibility of the resulting triazole-linked DNA. The correct function of this unnatural DNA linker in human cells is demonstrated here by using a click-linked gene encoding the fluorescent protein mCherry. Reverse transcription of mRNA isolated from these cells and subsequent sequencing of the mCherry cDNA shows error-free transcription. Nucleotide excision repair (NER) is shown to not play a role in the observed biocompatibility by using a NER-deficient human cell line. This is the first example of a non-natural DNA linker being functional in a eukaryotic cell.
Asunto(s)
ADN/síntesis química , ADN/genética , Transcripción Genética , Línea Celular , Química Clic , ADN/química , Reparación del ADN , Humanos , Proteínas Luminiscentes/genética , Biología Sintética , Triazoles/química , Proteína Fluorescente RojaRESUMEN
Hypoxia inducible factor-1 (HIF-1) is a heterodimeric transcription factor that acts as the master regulator of cellular response to reduced oxygen levels, thus playing a key role in the adaptation, survival, and progression of tumors. Here we report cyclo-CLLFVY, identified from a library of 3.2 million cyclic hexapeptides using a genetically encoded high-throughput screening platform, as an inhibitor of the HIF-1α/HIF-1ß protein-protein interaction in vitro and in cells. The identified compound inhibits HIF-1 dimerization and transcription activity by binding to the PAS-B domain of HIF-1α, reducing HIF-1-mediated hypoxia response signaling in a variety of cell lines, without affecting the function of the closely related HIF-2 isoform. The reported cyclic peptide demonstrates the utility of our high-throughput screening platform for the identification of protein-protein interaction inhibitors, and forms the starting point for the development of HIF-1 targeted cancer therapeutics.
Asunto(s)
Translocador Nuclear del Receptor de Aril Hidrocarburo/antagonistas & inhibidores , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Hipoxia , Péptidos Cíclicos/farmacología , Transducción de Señal/efectos de los fármacos , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Humanos , Células MCF-7 , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/química , Relación Estructura-ActividadRESUMEN
BACKGROUND: The genetic basis for avian to mammalian host switching in influenza A virus is largely unknown. The human A/HK/156/1997 (H5N1) virus that transmitted from poultry possesses NS1 gene mutations F103L + M106I that are virulence determinants in the mouse model of pneumonia; however their individual roles have not been determined. The emergent A/Shanghai/patient1/2013(H7N9)-like viruses also possess these mutations which may contribute to their virulence and ability to switch species. METHODS: NS1 mutant viruses were constructed by reverse genetics and site directed mutagenesis on human and mouse-adapted backbones. Mouse infections assessed virulence, virus yield, tissue infection, and IFN induction. NS1 protein properties were assessed for subcellular distribution, IFN antagonism (mouse and human), CPSF30 and RIG-I domain binding, host transcription (microarray); and the natural prevalence of 103L and 106I mutants was assessed. RESULTS: Each of the F103L and M106I mutations contributes additively to virulence to reduce the lethal dose by >800 and >3,200 fold respectively by mediating alveolar tissue infection with >100 fold increased infectious yields. The 106I NS1 mutant lost CPSF binding but the 103L mutant maintained binding that correlated with an increased general decrease in host gene expression in human but not mouse cells. Each mutation positively modulated the inhibition of IFN induction in mouse cells and activation of the IFN-ß promoter in human cells but not in combination in human cells indicating negative epistasis. Each of the F103L and M106I mutations restored a defect in cytoplasmic localization of H5N1 NS1 in mouse cells. Human H1N1 and H3N2 NS1 proteins bound to the CARD, helicase and RD RIG-I domains, whereas the H5N1 NS1 with the same consensus 103F and 106M mutations did not bind these domains, which was totally or partially restored by the M106I or F103L mutations respectively. CONCLUSIONS: The F103L and M106I mutations in the H5N1 NS1 protein each increased IFN antagonism and mediated interstitial pneumonia in mice that was associated with increased cytoplasmic localization and altered host factor binding. These mutations may contribute to the ability of previous HPAI H5N1 and recent LPAI H7N9 and H6N1 (NS1-103L+106M) viruses to switch hosts and cause disease in humans.
Asunto(s)
Factor de Especificidad de Desdoblamiento y Poliadenilación/metabolismo , ARN Helicasas DEAD-box/metabolismo , Subtipo H5N1 del Virus de la Influenza A/inmunología , Subtipo H5N1 del Virus de la Influenza A/patogenicidad , Interferones/antagonistas & inhibidores , Mutación Missense , Proteínas no Estructurales Virales/metabolismo , Sustitución de Aminoácidos , Animales , Proteína 58 DEAD Box , Femenino , Interacciones Huésped-Patógeno , Humanos , Subtipo H5N1 del Virus de la Influenza A/aislamiento & purificación , Pulmón/patología , Pulmón/virología , Enfermedades Pulmonares Intersticiales/patología , Enfermedades Pulmonares Intersticiales/virología , Ratones , Mutagénesis Sitio-Dirigida , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Genética Inversa , Proteínas no Estructurales Virales/genética , Virulencia , Factores de Virulencia/genética , Factores de Virulencia/metabolismoRESUMEN
The metabolic pathways through which p53 functions as a potent tumor suppressor are incompletely understood. Here we report that, by associating with the Vitamin D receptor (VDR), p53 induces numerous genes encoding enzymes for peroxisomal fatty acid ß-oxidation (FAO). This leads to increased cytosolic acetyl-CoA levels and acetylation of the enzyme 5-Aminoimidazole-4-Carboxamide Ribonucleotide Formyltransferase/IMP Cyclohydrolase (ATIC), which catalyzes the last two steps in the purine biosynthetic pathway. This acetylation step, mediated by lysine acetyltransferase 2B (KAT2B), occurs at ATIC Lys 266, dramatically inhibits ATIC activity, and inversely correlates with colorectal cancer (CRC) tumor growth in vitro and in vivo, and acetylation of ATIC is downregulated in human CRC samples. p53-deficient CRCs with high levels of ATIC is more susceptible to ATIC inhibition. Collectively, these findings link p53 to peroxisomal FAO, purine biosynthesis, and CRC pathogenesis in a manner that is regulated by the levels of ATIC acetylation.
Asunto(s)
Transferasas de Hidroximetilo y Formilo , Proteína p53 Supresora de Tumor , Humanos , Purinas , Ácidos GrasosRESUMEN
P110α is a member of the phosphoinositide 3-kinase (PI3K) enzyme family that functions downstream of RAS. RAS proteins contribute to the activation of p110α by interacting directly with its RAS binding domain (RBD), resulting in the promotion of many cellular functions such as cell growth, proliferation and survival. Previous work from our lab has highlighted the importance of the p110α/RAS interaction in tumour initiation and growth. Here we report the discovery and characterisation of a cyclic peptide inhibitor (cyclo-CRVLIR) that interacts with the p110α-RBD and blocks its interaction with KRAS. cyclo-CRVLIR was discovered by screening a "split-intein cyclisation of peptides and proteins" (SICLOPPS) cyclic peptide library. The primary cyclic peptide hit from the screen initially showed a weak affinity for the p110α-RBD (Kd about 360 µM). However, two rounds of amino acid substitution led to cyclo-CRVLIR, with an improved affinity for p110α-RBD in the low µM (Kd 3 µM). We show that cyclo-CRVLIR binds selectively to the p110α-RBD but not to KRAS or the structurally-related RAF-RBD. Further, using biophysical, biochemical and cellular assays, we show that cyclo-CRVLIR effectively blocks the p110α/KRAS interaction in a dose dependent manner and reduces phospho-AKT levels in several oncogenic KRAS cell lines.
Asunto(s)
Fosfatidilinositol 3-Quinasa , Transducción de Señal , Fosfatidilinositol 3-Quinasa/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismoRESUMEN
Aminoimidazole carboxamide ribonucleotide transformylase/inosine monophosphate cyclohydrolase (ATIC) is a bifunctional homodimeric enzyme that catalyzes the last two steps of de novo purine biosynthesis. Homodimerization of ATIC, a protein-protein interaction with an interface of over 5000 Å(2), is required for its aminoimidazole carboxamide ribonucleotide (AICAR) transformylase activity, with the active sites forming at the interface of the interacting proteins. Here, we report the development of a small-molecule inhibitor of AICAR transformylase that functions by preventing the homodimerization of ATIC. The compound is derived from a previously reported cyclic hexapeptide inhibitor of AICAR transformylase (with a K(i) of 17 µM), identified by high-throughput screening. The active motif of the cyclic peptide is identified as an arginine-tyrosine dipeptide, a capped analogue of which inhibits AICAR transformylase with a K(i) value of 84 µM. A library of nonnatural analogues of this dipeptide was designed, synthesized, and assayed. The most potent compound inhibits AICAR transformylase with a K(i) value of 685 nM, a 25-fold improvement in activity from the parent cyclic peptide. The potential for this AICAR transformylase inhibitor in cancer therapy was assessed by studying its effect on the proliferation of a model breast cancer cell line. Using a nonradioactive proliferation assay and live cell imaging, a dose-dependent reduction in cell numbers and cell division rates was observed in cells treated with our ATIC dimerization inhibitor.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Inhibidores Enzimáticos/farmacología , Péptidos Cíclicos/farmacología , Fosforribosilaminoimidazolcarboxamida-Formiltransferasa/química , Multimerización de Proteína/efectos de los fármacos , Antineoplásicos/síntesis química , Antineoplásicos/química , Dominio Catalítico/efectos de los fármacos , Recuento de Células , División Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Femenino , Ensayos Analíticos de Alto Rendimiento , Humanos , Células MCF-7 , Estructura Molecular , Peso Molecular , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/química , Fosforribosilaminoimidazolcarboxamida-Formiltransferasa/antagonistas & inhibidores , Fosforribosilaminoimidazolcarboxamida-Formiltransferasa/metabolismo , Relación Estructura-ActividadRESUMEN
The human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS), relies heavily on protein-protein interactions in almost every step of its lifecycle. Targeting these interactions, especially those between virus and host proteins, is increasingly viewed as an ideal avenue for the design and development of new therapeutics. In this tutorial review, we outline the lifecycle of HIV and describe some of the protein-protein interactions that control and regulate each step of this process, also detailing efforts to develop therapies that target these interactions.
Asunto(s)
VIH/metabolismo , Proteínas del Virus de la Inmunodeficiencia Humana/metabolismo , VIH/enzimología , Proteína gp120 de Envoltorio del VIH/química , Integrasa de VIH/química , Proteasa del VIH/química , Proteasa del VIH/genética , Transcriptasa Inversa del VIH/química , Proteínas del Virus de la Inmunodeficiencia Humana/antagonistas & inhibidores , Humanos , Unión Proteica , Replicación ViralRESUMEN
The adaptation of tumours to hypoxia is critical for their survival and growth. The high proliferation rate of solid tumours causes the continuous outstripping of the oxygen supply provided by the local vasculature, resulting in hypoxic regions within the tumour. Hypoxia inducible factor (HIF) is the key mediator of cellular response to hypoxia, activating the expression of multiple genes that participate in angiogenesis, iron metabolism, glycolysis, glucose transport and cell proliferation and survival. The critical role of the hypoxia response network and HIF in cancer has resulted in it being viewed as an ideal target for small molecule intervention. In this tutorial review we discuss the central role of HIF in the adaptation of tumours to a hypoxic environment, going on to describe recent attempts at developing small molecules that disrupt this pathway and their potential for use as the next generation anticancer therapeutics.