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Youngtae Chang - One of the best experts on this subject based on the ideXlab platform.
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target identification a challenging step in forward Chemical Genetics
Interdisciplinary Bio Central, 2011Co-Authors: Raj Kumar Das, Animesh Samanta, Krishnakanta Ghosh, Duanting Zhai, Cheryl Leong, Youngtae ChangAbstract:Investigation of the genetic functions in complex biological systems is a challenging step in recent year. Hence, several valuable and interesting research projects have been developed with novel ideas to find out the unknown functions of genes or proteins. To validate the applicability of their novel ideas, various approaches are built up. To date, the most promising and commonly used approach for discovering the target proteins from biological system using small molecule is well known a forward Chemical Genetics which is considered to be more convenient than the classical Genetics. Although, the forward Chemical Genetics consists of the three basic components, the target identification is the most challenging step to Chemical biology researchers. Hence, the diverse target identification methods have been developed and adopted to disclose the small molecule bound protein. Herein, in this review, we briefly described the first two parts Chemical toolbox and screening, and then the target identifications in forward Chemical Genetics are thoroughly described along with the illustrative real example case study. In the tabular form, the different biological active small molecules which are the successful examples of target identifications are accounted in this research review.
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Wiley Encyclopedia of Chemical Biology - Forward Chemical Genetics
Wiley Encyclopedia of Chemical Biology, 2008Co-Authors: Youngtae ChangAbstract:With the successful results of the Human Genome Project, we are now faced with the problem of handling numerous gene targets whose functions remain to be studied; this challenge is being undertaken by the field known as functional genomics. Chemical Genetics is an emerging new paradigm to attack this challenging problem, of which there are two approaches: forward and reverse. Although reverse Chemical Genetics uses a “cause-to-effect” approach, forward Chemical Genetics uses an “effect-to-cause” approach. As opposed to conventional Genetics where gene knock-outs or overexpression, forward Chemical Genetics uses a small-molecule library to produce a novel phenotype that eventually is employed in the elucidation of gene function. Compared with conventional Genetics, Chemical Genetics holds several unique advantages. A successful forward genetic study provides not only knowledge about a novel gene's function, but also it provides a small molecule on/off switch that can regulate biologic processes. These small molecules will be extremely useful biologic probes as well as potential new drug candidates. Three main components make up forward Chemical Genetics: 1) Chemical toolbox generation, 2) phenotypic screening, and 3) target identification. Although all three components require additional refinement, target identification poses the greatest challenge. Herein, the general concepts of Chemical Genetics, with a focus on the forward approach, and the technical overviews for each component are described.
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Tagged Small Molecule Library Approach for Facilitated Chemical Genetics
Accounts of chemical research, 2007Co-Authors: Young Hoon Ahn, Youngtae ChangAbstract:Chemical Genetics is a powerful method which utilizes small molecule regulators to reveal the molecular basis of diverse biological processes. However, the current Chemical genetic approach sometimes meets a serious bottleneck during the process of target identification. One faces difficulty in conjugating the active compound to an affinity matrix without losing or reducing its activity that leads to laborious structure‐activity relationship (SAR) studies. To facilitate this process, we have developed a tagged triazine library containing a built-in linker that provides a straightforward transition from phenotypic screening to target identification. A strategy for constructinig a tagged library and applications with a streamlined target identification and subsequent mechanistic study are discussed in this Account.
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tagged library approach facilitates forward Chemical Genetics
Molecular BioSystems, 2007Co-Authors: Yun Kyung Kim, Youngtae ChangAbstract:Forward Chemical Genetics has been highlighted as a new method for the study of various biological pathways using exogenous ligands. However, limited success in the field has demonstrated that, in many cases, it is not feasible to determine the protein targets of small-molecule probes. Identifying protein targets is an integral part of forward Chemical Genetics and is also the most challenging. Over the past decade, several bioChemical and genetic methods have been developed to facilitate target identification processes. Even so, one of the major difficulties is that these methods require the Chemical modification of active compounds, with a significant amount of structure-activity relationship (SAR) study to ensure that the small-molecule tags do not compromise bioactivity. In this article, we will highlight a new strategy for small molecule libraries that have built-in linkers in order to avoid this well-known problem and demonstrate their successful use in forward Chemical Genetics.
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forward Chemical Genetics library scaffold design
Combinatorial Chemistry & High Throughput Screening, 2004Co-Authors: Sonya M Khersonsky, Youngtae ChangAbstract:With the unraveling of the entire human genome, it has become imperative to understand the function of the gene products, proteins. Within the past several years, Chemical Genetics has gained recognition as a powerful approach to study protein function by using small molecules as gene knock-out or knock-in mimics. Forward Chemical Genetics is a three-step process; the design and synthesis of a small molecule library represents the first step followed secondly by the search for novel phenotypes and then by isolation and identification of target protein(s). This review will focus on the first step, the design of the scaffold for small molecule libraries. It will also examine the connection between the choice of a scaffold and the propensity of that library to demonstrate enhanced biological activity when tested in certain cellular systems.
Craig M. Crews - One of the best experts on this subject based on the ideXlab platform.
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Chemical Genetics: exploring the role of the proteasome in cell biology using natural products and other small molecule proteasome inhibitors.
Journal of medicinal chemistry, 2008Co-Authors: Kyung Bo Kim, Craig M. CrewsAbstract:In the era of systemic proteomics, temporal and spatial control of protein functions has become very important in the investigation of complex biological processes in vivo. While traditional genetic manipulations have provided a powerful tool to study protein function, these applications are limited by the possibility that some mutant phenotypes may be due to compensatory responses that occur during development. In addition, gene knockout models that are embryonic lethal are not amenable to study disease processes that occur in the adult animal. Moreover, the inhibition of the target gene’s function is often irreversible, and thus, the desired biological effect(s) cannot be readily regulated. This makes it difficult to dissect the precise role of proteins in complex signaling pathways. Recently, small interfering RNA (siRNAa) has been widely used to modulate protein function at the RNA level.1 However, this technique offers limited temporal control of gene expression. Difficulties with the nonspecificity and delivery of siRNAs have also been major concerns. The use of small-molecule probes is one way to complement these genetic approaches. Most biologically active small molecules including natural products exert their activities via inhibition of specific biological processes. In comparison to the classical genetic approach, this small molecule approach easily affords more temporal and spatial control of targeted biological events. A small molecule approach, being complementary to the classical genetic approach, is thus fittingly dubbed “Chemical Genetics”.2 Although many areas of biology have benefited from the Chemical Genetics approach, few have been more broadly and significantly impacted than the biology and biochemistry of the proteasome.
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Chemical Genetics: A Small Molecule Approach to Neurobiology
Neuron, 2002Co-Authors: Brian Koh, Craig M. CrewsAbstract:Chemical Genetics, or the specific modulation of cellular systems by small molecules, has complemented classical genetic analysis throughout the history of neurobiology. We outline several of its contributions to the understanding of ion channel biology, heat and cold signal transduction, sleep and diurnal rhythm regulation, effects of immunophilin ligands, and cell surface oligosaccharides with respect to neurobiology.
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Chemical Genetics: exploring and controlling cellular processes with Chemical probes.
Trends in biochemical sciences, 1999Co-Authors: Craig M. Crews, Ute SplittgerberAbstract:Abstract The new field of Chemical biology brings together chemists and biologists who are seeking to understand and mimic the natural world. One research strategy in this new field is the development of biologically active small molecules as molecular probes. This approach, which has been called ‘Chemical' Genetics, has allowed elucidation of several pathways that have been difficult to study using traditional genetic approaches.
Zhao Yang - One of the best experts on this subject based on the ideXlab platform.
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Plant Chemical Genetics: A Novel Approach to Plant Genetics Researches
Plant Physiology, 2011Co-Authors: Zhao YangAbstract:Chemical Genetics approaches,also known as Chemical genomics,using biologically active small molecules perturb interacting proteins involved in a certain biological process of a biological subject in question.It is complement and extension of conventional Genetics approaches in term of methodology.The application of Chemical Genetics methods in plant sciences,termed as plant Chemical Genetics,in recent years,has started to answer some long time questions in this research field,because it,as a method itself,has such characters and advantages in dealing with genetic problems like,genetic redundancy and genetic mutation lethality,as well as providing specific genetic perturbations in term of strength and time.This article describes the principles of plant Chemical Genetics including some advantages and characteristic perspectives as research approaches.
Maurizio Pellecchia - One of the best experts on this subject based on the ideXlab platform.
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SAR by ILOEs: An NMR‐Based Approach to Reverse Chemical Genetics
Chemistry (Weinheim an der Bergstrasse Germany), 2006Co-Authors: Barbara Becattini, Maurizio PellecchiaAbstract:Reverse Chemical Genetics is an emerging technique that makes use of small molecule inhibitors to characterize how a protein functions. In this regard, we have developed an NMR-based approach (SAR by ILOEs) that enables the identification of high affinity ligands for a given protein target without the need of a specific assay. Our approach is of general applicability and could result very powerful in reverse Chemical-Genetics studies, target validation, and lead discovery. We report a recent application on the design and synthesis of compounds that inhibit protein-membrane interactions.
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sar by iloes an nmr based approach to reverse Chemical Genetics
Chemistry: A European Journal, 2006Co-Authors: Barbara Becattini, Maurizio PellecchiaAbstract:Reverse Chemical Genetics is an emerging technique that makes use of small molecule inhibitors to characterize how a protein functions. In this regard, we have developed an NMR-based approach (SAR by ILOEs) that enables the identification of high affinity ligands for a given protein target without the need of a specific assay. Our approach is of general applicability and could result very powerful in reverse Chemical-Genetics studies, target validation, and lead discovery. We report a recent application on the design and synthesis of compounds that inhibit protein-membrane interactions.
Thomas U. Mayer - One of the best experts on this subject based on the ideXlab platform.
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Chemical Genetics Approach to Engineer Kinesins with Sensitivity towards a Small-Molecule Inhibitor of Eg5.
Chembiochem : a European journal of chemical biology, 2016Co-Authors: Martin M Möckel, Corinna Hund, Thomas U. MayerAbstract:Due to their fast and often reversible mode of action, small molecules are ideally suited to dissect biological processes. Yet, the validity of small-molecule studies is intimately tied to the specificity of the applied compounds, thus imposing a great challenge to screens for novel inhibitors. Here, we applied a Chemical-Genetics approach to render kinesin motor proteins sensitive to inhibition by the well-characterized small molecule S-Trityl-l-cysteine (STLC). STLC specifically inhibits the kinesin Eg5 through binding to a known allosteric site within the motor domain. Transfer of this allosteric binding site into the motor domain of the human kinesins Kif3A and Kif4A sensitizes them towards STLC. Single-molecule microscopy analyses confirmed that STLC inhibits the movement of chimeric but not wild-type Kif4A along microtubules. Thus, our proof-of-concept study revealed that this Chemical-genetic approach provides a powerful strategy to specifically inhibit kinesins in vitro for which small-molecule inhibitors are not yet available.
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Chemical Genetics: reshaping biology through chemistry.
HFSP journal, 2007Co-Authors: Stefan Florian, Stefan Hümmer, Mario Catarinella, Thomas U. MayerAbstract:To understand biological processes, biologists typically study how perturbations of protein functions affect the phenotype. Protein activity in living cells can be influenced in many different ways: by manipulation of the genomic information, by injecting inhibitory antibodies, or, more recently, by the use of ribonucleic acid-medicated interference (RNAi). All these methods have proven to be extremely helpful, as they possess a high degree of specificity. However, they are less suitable for experiments requiring precise timing and fast reversibility of the perturbation. The advantage of small molecules is that they specifically interact with their target on a fast time scale and often in a reversible manner. In the last 15 years, this approach, termed “Chemical Genetics,” has received a lot of attention. The term Genetics pays tribute to the analogy between Chemical Genetics and the classic genetic approach, where manipulations at the gene level are used to draw conclusions about the function of the corresponding protein. Chemical Genetics has only recently been used as a systematic approach in biology. The term was coined in the 1990’s, when combinatorial chemistry was developed as a fast method to synthesize large compound libraries [Mitchison (1994) “Towards a pharmacological Genetics,” Chem. Biol. 1, 3–6; Schreiber (1998) “Chemical Genetics resulting from a passion for synthetic organic chemistry,” Bioorg. Med. Chem. 6, 1127–1152].
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Chemical Genetics: tailoring tools for cell biology
Trends in cell biology, 2003Co-Authors: Thomas U. MayerAbstract:Chemical Genetics is a research approach that uses small molecules as probes to study protein functions in cells or whole organisms. Here, I review the parallels between classical genetic and Chemical-genetic approaches and discuss the merits of small molecules to dissect dynamic cellular processes. I then consider the pros and cons of different screening approaches and specify strategies aimed at identifying and validating cellular target proteins. Finally, I highlight the impact of Chemical Genetics on our current understanding of cell biology and its potential for the future.