Proteomic methods for drug target discovery

Sleno, Lekha; Emili, Andrew

doi:10.1016/j.cbpa.2008.01.022

Cited by 122 publications

(89 citation statements)

References 44 publications

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“…They can be applied not only for the better understanding of physiological processes that take place in a biological sample; they are also useful to understand disease processes (Horgan & Kenny 2011). These techniques, integrated, could also help to discover new therapeutics and the targets for its action (Ulrich-Merzenich et al 2007, Ahn & Wang 2008, Sleno & Emili 2008, Caberlotto & Lauria 2015, along with enzymes and other proteins or metabolites of clinical or industrial interest from different sources (Fridman & Pichersky 2005, Rochfort 2005, Tang & Zhao 2009, O'Flaherty & Klaenhammer 2011.…”

Section: Omic Technologies and Strategies On Pycnoporus Genusmentioning

confidence: 99%

Mycosphere Essay 11: Fungi of Pycnoporus: morphological and molecular identification, worldwide distribution and biotechnological potential

Téllez‐Téllez¹

2016

Mycosphere

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Fungi of the Pycnoporus are efficient degraders of lignocellulosic materials, so they are classified as white-rot fungi. A distinctive feature is its color ranging from orange to bright red, attributed to cinnabarin, cinnabarinic acid and tramesanguin mainly, compounds to which have been attributed some biological activities. This review updates the reports on morphological characteristics, the distribution of species of Pycnoporus, and the advantages of molecular techniques in species identification. Furthermore, the potential biotechnological applications of these fungi are mentioned with a focus on insecticidal and antibacterial activities. In addition, the production of hydrolytic enzymes including cellulases, hemicellulases, pectinases are discussed as well as phenoloxidases such as laccases and their participation in the degradation of agro-industrial waste.

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Section: Omic Technologies and Strategies On Pycnoporus Genusmentioning

confidence: 99%

Mycosphere Essay 11: Fungi of Pycnoporus: morphological and molecular identification, worldwide distribution and biotechnological potential

Téllez‐Téllez¹

2016

Mycosphere

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“…We recently developed an in silico approach based on fold recognition methods to identify prospective new mART members from bacterial genomes (13). These newly discovered toxins can now be exploited as targets in the development of new antivirulence therapeutics for treating bacterial diseases and infections (9,29).Here, we focus on two DT-group mARTs targeting elongation factor 2-ExoA, a well-characterized factor produced by P. aeruginosa, and cholix, a new mART toxin recently identified with our in silico approach from V. cholerae (16)-which, along with diphtheria toxin, show nearly identical enzyme activities and inhibitor specificities (2,16,31,35,36). Using the 1.25-Å cocrystal structure of cholix toxin with PJ34 [N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino)acet-* Corresponding author.…”

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confidence: 99%

Newly Discovered and Characterized Antivirulence Compounds Inhibit Bacterial Mono-ADP-Ribosyltransferase Toxins

Turgeon

Jørgensen

Visschedyk

et al. 2011

Antimicrob Agents Chemother

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The mono-ADP-ribosyltransferase toxins are bacterial virulence factors that contribute to many disease states in plants, animals, and humans. These toxins function as enzymes that target various host proteins and covalently attach an ADP-ribose moiety that alters target protein function. We tested compounds from a virtual screen of commercially available compounds combined with a directed poly(ADP-ribose) polymerase (PARP) inhibitor library and found several compounds that bind tightly and inhibit toxins from Pseudomonas aeruginosa and Vibrio cholerae. The most efficacious compounds completely protected human lung epithelial cells against the cytotoxicity of these bacterial virulence factors. Moreover, we determined high-resolution crystal structures of the best inhibitors in complex with cholix toxin to reveal important criteria for inhibitor binding and mechanism of action. These results provide new insight into development of antivirulence compounds for treating many bacterial diseases.Bacteria use virulence factors as tools to facilitate disease in plants, animals, and humans (14,26,30,34); one strategy to combat infection is to inhibit these factors by small-molecule therapy, thereby helping to neutralize the offending microbe (5,6,12,19,22). It is now generally appreciated that an antivirulence approach is a powerful alternative strategy for antibacterial treatment and vaccine development (27) and that it may require multiple tactics to resolve the current drug resistance dilemma (6,8). Antivirulence compounds offer significant advantages over conventional antibiotics since these inhibitors are directed toward specific mechanisms (targets) in the offending pathogen that promote infection rather than against an essential metabolic factor (12). Neutralizing the cytotoxic properties of virulence factors from microorganisms without threatening their survival offers reduced selection pressure, making the induction of drug resistance mutations less likely (6). Additionally, virulence-specific therapeutics avoid the undesirable effects on the host microbiota that are associated with current antibiotics.The mono-ADP-ribosyltransferase (mART) family is a group of toxic bacterial enzymes, some of which possess a long history against human civilization. The best-characterized and wellknown members of this lethal family are cholera toxin (CT) from Vibrio cholerae, diphtheria toxin (DT) produced by Corynebacterium diphtheriae, pertussis toxin (PT) from Bordella pertussis, heat-labile enterotoxin from Escherichia coli, C3-like exoenzyme produced by Clostridium botulinum and Clostridium limosum, and exotoxin A (ExoA) from Pseudomonas aeruginosa. These enzymes act on NAD ϩ and facilitate the scission of the glycosidic bond (C-N) between nicotinamide and its conjugated ribose followed by the transfer of the ADPribose group to a nucleophilic residue on a target macromolecule (35). This family can be divided into the CT and DT groups. The CT group consists of an ExoS-like subgroup (enzymatic A domain alone or paired with ano...

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“…A fundamental task in biology is to characterise protein constituents present within different subcellular compartments or macromolecular complexes (1)(2)(3)(4)(5). This is essential for understanding how these components interact to perform various cellular functions.…”

Section: Introductionmentioning

confidence: 99%

“…For most proteins this goal cannot be achieved by direct utilisation of information from genome sequencing projects, since there is limited knowledge of motifs that target proteins to particular subcellular environments, determine protein functions or that allow them to interact with binding partners. Use of subproteomic approaches, such as 2D-SDS-PAGE followed by mass spectroscopy or liquid chromatography combined with mass spectroscopy, provides one solution for profiling of proteins present in particular cellular compartments or macromolecular complexes (3)(4)(5)(6)(7). However, such techniques are often hampered by poor reproducibility, limited sensitivity, poor dynamic range and inadequate resolution of large (>100 kDa) or hydrophobic proteins.…”

Section: Introductionmentioning

confidence: 99%

‘Shotgun immunological’ approach for analysis of a complex subcellular system

Mackrill

England²,

Flucher³

et al. 2009

Int J Mol Med

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Abstract. Subsets of proteins present and the interactions between them are fundamental determinants of the properties of complex biological systems. Monoclonal antibodies (mAbs) are highly versatile tools for characterisation of such systems, being employed to analyse the structures, functions, locations and macromolecular interactions of their cognate antigens. However, production of mAbs using hybridoma technology is time-consuming, technically demanding and uses a large amount of target material. The study presented here demonstrates that a panel of synthetic single-chain fragment variable (scFv) mAbs recognising protein components of isolated terminal cisternae sarcoplasmic reticulum membranes can be rapidly selected by bacteriophage display, using small quantities of target material. The panel of scFv mAbs isolated proved useful in a wide range of immunological applications, including immunoblot, indirect immunofluorescence microscopy and for immunoprecipitation combined with identification of targets by mass spectroscopy. Such 'shotgun immunological' strategies will prove effective in characterising novel constituents of, as well as for investigating proteinprotein interactions within, macromolecular structures isolated from biological systems.

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Proteomic methods for drug target discovery

Cited by 122 publications

References 44 publications

Mycosphere Essay 11: Fungi of Pycnoporus: morphological and molecular identification, worldwide distribution and biotechnological potential

Mycosphere Essay 11: Fungi of Pycnoporus: morphological and molecular identification, worldwide distribution and biotechnological potential

Newly Discovered and Characterized Antivirulence Compounds Inhibit Bacterial Mono-ADP-Ribosyltransferase Toxins

‘Shotgun immunological’ approach for analysis of a complex subcellular system

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