From protein interaction networks to novel therapeutic strategies

Joint IRB-BSC program in Computational Biology, Institute for Research in Biomedicine, Barcelona, Spain.
International Union of Biochemistry and Molecular Biology Life (Impact Factor: 3.14). 06/2012; 64(6):529-37. DOI: 10.1002/iub.1040
Source: PubMed

ABSTRACT Cellular mechanisms that sustain health or contribute to disease emerge mostly from the complex interplay among various molecular entities. To understand the underlying relationships between genotype, environment and phenotype, one has to consider the intricate and nonsequential interaction patterns formed between the different sets of cellular players. Biological networks capture a variety of molecular interactions and thus provide an excellent opportunity to consider physiological characteristics of individual molecules within their cellular context. In particular, the concept of network biology and its applications contributed largely to recent advances in biomedical research. In this review, we show (i) how biological networks, i.e., protein-protein interaction networks, facilitate the understanding of pathogenic mechanisms that trigger the onset and progression of diseases and (ii) how this knowledge can be translated into effective diagnostic and therapeutic strategies. In particular, we focus on the impact of network pharmacological concepts that go beyond the classical view on individual drugs and targets aiming for combinational therapies with improved clinical efficacy and reduced safety risks.

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    • "Evolution of such methods has allowed the dynamic detection of PPI in living cells (Xu et al., 1999; Coulon et al., 2008; Lee et al., 2010; Quiñones et al., 2012) and nowadays in whole living organisms (Subramanian et al., 2004; Audet et al., 2010). Following this evolution scheme, PPI pathways have been deciphered and furthermore organized in higher protein networks ranging from PPI taking place in molecular complexes, to entire organelles and to whole organisms (Coulon et al., 2008; Chautard et al., 2009; Jaeger and Aloy, 2012). Our current knowledge of these PPI networks has further increased in recent years with the emerging idea that more than PPI networks themselves, the biological context in which they occur is important. "
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    ABSTRACT: Each step of the cell life and its response or adaptation to its environment are mediated by a network of protein/protein interactions termed "interactome." Our knowledge of this network keeps growing due to the development of sensitive techniques devoted to study these interactions. The bioluminescence resonance energy transfer (BRET) technique was primarily developed to allow the dynamic monitoring of protein/protein interactions (PPI) in living cells, and has widely been used to study receptor activation by intra- or extra-molecular conformational changes within receptors and activated complexes in mammal cells. Some interactions are described as crucial in human pathological processes, and a new class of drugs targeting them has recently emerged. The BRET method is well suited to identify inhibitors of PPI and here is described why and how to set up and optimize a high throughput screening assay based on BRET to search for such inhibitory compounds. The different parameters to take into account when developing such BRET assays in mammal cells are reviewed to give general guidelines: considerations on the targeted interaction, choice of BRET version, inducibility of the interaction, kinetic of the monitored interaction, and of the BRET reading, influence of substrate concentration, number of cells and medium composition used on the Z' factor, and expected interferences from colored or fluorescent compounds.
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    ABSTRACT: Protein-protein interactions drive biological processes. They are critical for all intra and extra cellular functions, and the technologies to analyse them are widely applied throughout the various fields of biological sciences. This article takes an in depth view of some common principles of cellular regulation and provides a detailed account of approaches required to comprehensively map signalling protein-protein interactions in any particular cellular system or condition. We provide a critical review of benefits and disadvantages of the yeast-two-hybrid method and affinity purification coupled with mass spectrometric (AP-MS) procedures for identification of signalling protein-protein interactions. In particular we emphasize the quantitative and qualitative differences between tandem affinity (TAP) and one-step purification (such as Flag- and Strep-tag) methods. Albeit applicable to all type of interaction studies, a special section is devoted in this review to aspects that should be considered when attempting to identify signalling protein interactions that often are transient and weak by nature. Finally, we discuss shotgun and quantitative information that can be gleaned by MS-coupled methods for analysis of multiprotein complexes.
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    ABSTRACT: Metabolism represents the 'sharp end' of systems biology, because changes in metabolite concentrations are necessarily amplified relative to changes in the transcriptome, proteome and enzyme activities, which can be modulated by drugs. To understand such behaviour, we therefore need (and increasingly have) reliable consensus ('community') models of the human metabolic network that include the important transporters. Small molecule 'drug' transporters are in fact metabolite transporters, because drugs bear structural similarities to metabolites known from the network reconstructions and from measurements of the metabolome. Recon2 represents the present state-of-the-art human metabolic network reconstruction; it can predict inter alia: (i) the effects of inborn errors of metabolism; (ii) which metabolites are exometabolites; and (iii) how metabolism varies between tissues and cellular compartments. However, even these qualitative network models are not yet complete. As our understanding improves so do we recognise more clearly the need for a systems (poly)pharmacology.
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