• Title, Summary, Keyword: target molecule

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Single-molecule fluorescence measurements reveal the reaction mechanisms of the core-RISC, composed of human Argonaute 2 and a guide RNA

  • Jo, Myung Hyun;Song, Ji-Joon;Hohng, Sungchul
    • BMB Reports
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    • v.48 no.12
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    • pp.643-644
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    • 2015
  • In eukaryotes, small RNAs play important roles in both gene regulation and resistance to viral infection. Argonaute proteins have been identified as a key component of the effector complexes of various RNA-silencing pathways, but the mechanistic roles of Argonaute proteins in these pathways are not clearly understood. To address this question, we performed single-molecule fluorescence experiments using an RNA-induced silencing complex (core-RISC) composed of a small RNA and human Argonaute 2. We found that target binding of core-RISC starts at the seed region of the guide RNA. After target binding, four distinct reactions followed: target cleavage, transient binding, stable binding, and Argonaute unloading. Target cleavage required extensive sequence complementarity and accelerated core-RISC dissociation for recycling. In contrast, the stable binding of core-RISC to target RNAs required seed-match only, suggesting a potential explanation for the seed-match rule of microRNA (miRNA) target selection.

Lipid A as a Drug Target and Therapeutic Molecule

  • Joo, Sang Hoon
    • Biomolecules & Therapeutics
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    • v.23 no.6
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    • pp.510-516
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    • 2015
  • In this review, lipid A, from its discovery to recent findings, is presented as a drug target and therapeutic molecule. First, the biosynthetic pathway for lipid A, the Raetz pathway, serves as a good drug target for antibiotic development. Several assay methods used to screen for inhibitors of lipid A synthesis will be presented, and some of the promising lead compounds will be described. Second, utilization of lipid A biosynthetic pathways by various bacterial species can generate modified lipid A molecules with therapeutic value.

Prodrug and Antedrug: Two Diametrical Approaches in Designing Safer Drugs

  • Lee, Henry-J.;Cooperwood, John-S.;You, Zhengqing;Ko, Dong-Hoon
    • Archives of Pharmacal Research
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    • v.25 no.2
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    • pp.111-136
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    • 2002
  • The prodrug and antedrug concepts, which were developed to overcome the physical and pharmacological shortcomings of various therapeutic classes of agents, employ diametrically different metabolic transformations. The prodrug undergoes a predictable metabolic activation prior to exhibiting its pharmacological effects in a target tissue while the antedrug undergoes metabolic deactivation in the systemic circulation upon leaving a target tissue. An increased therapeutic index is the aspiration for both approaches in designing as well as evaluation criteria. The recent research endeavors of prodrugs include the gene-directed and antibody-directed enzymatic activation of a molecule in a targeted tissue, organ specific delivery, improved bioavailabilities and cellular penetration of nucleotides. As for antedrugs, emphasis in research has been based upon the design and synthesis of systemically inactive molecule by incorporating a metabolically labile functional group into an active molecule.

Chemically Induced Cellular Proteolysis: An Emerging Therapeutic Strategy for Undruggable Targets

  • Moon, Seonghyeon;Lee, Byung-Hoon
    • Molecules and Cells
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    • v.41 no.11
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    • pp.933-942
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    • 2018
  • Traditionally, small-molecule or antibody-based therapies against human diseases have been designed to inhibit the enzymatic activity or compete for the ligand binding sites of pathological target proteins. Despite its demonstrated effectiveness, such as in cancer treatment, this approach is often limited by recurring drug resistance. More importantly, not all molecular targets are enzymes or receptors with druggable 'hot spots' that can be directly occupied by active site-directed inhibitors. Recently, a promising new paradigm has been created, in which small-molecule chemicals harness the naturally occurring protein quality control machinery of the ubiquitin-proteasome system to specifically eradicate disease-causing proteins in cells. Such 'chemically induced protein degradation' may provide unprecedented opportunities for targeting proteins that are inherently undruggable, such as structural scaffolds and other non-enzymatic molecules, for therapeutic purposes. This review focuses on surveying recent progress in developing E3-guided proteolysis-targeting chimeras (PROTACs) and small-molecule chemical modulators of deubiquitinating enzymes upstream of or on the proteasome.

Strategies and Advancement in Antibody-Drug Conjugate Optimization for Targeted Cancer Therapeutics

  • Kim, Eunhee G.;Kim, Kristine M.
    • Biomolecules & Therapeutics
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    • v.23 no.6
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    • pp.493-509
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    • 2015
  • Antibody-drug conjugates utilize the antibody as a delivery vehicle for highly potent cytotoxic molecules with specificity for tumor-associated antigens for cancer therapy. Critical parameters that govern successful antibody-drug conjugate development for clinical use include the selection of the tumor target antigen, the antibody against the target, the cytotoxic molecule, the linker bridging the cytotoxic molecule and the antibody, and the conjugation chemistry used for the attachment of the cytotoxic molecule to the antibody. Advancements in these core antibody-drug conjugate technology are reflected by recent approval of Adectris$^{(R)}$(anti-CD30-drug conjugate) and Kadcyla$^{(R)}$(anti-HER2 drug conjugate). The potential approval of an anti-CD22 conjugate and promising new clinical data for anti-CD19 and anti-CD33 conjugates are additional advancements. Enrichment of antibody-drug conjugates with newly developed potent cytotoxic molecules and linkers are also in the pipeline for various tumor targets. However, the complexity of antibody-drug conjugate components, conjugation methods, and off-target toxicities still pose challenges for the strategic design of antibody-drug conjugates to achieve their fullest therapeutic potential. This review will discuss the emergence of clinical antibody-drug conjugates, current trends in optimization strategies, and recent study results for antibody-drug conjugates that have incorporated the latest optimization strategies. Future challenges and perspectives toward making antibody-drug conjugates more amendable for broader disease indications are also discussed.

Detection of Molecules using the Nanoparticle Arrays (나노입자 배열을 이용한 분자 검출)

  • Ha, Dong-Han;Kim, Sang-Hun;Yun, Yong-Ju;Park, Hyung-Ju;Yun, Wan-Soo
    • Proceedings of the KSME Conference
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    • pp.1617-1622
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    • 2008
  • We report a new molecular detection process which measures the changes in the plasmon resonance peaks of periodic Au nanoparticle arrays fabricated using the electron beam lithography. As the Au nanoparticle arrays are modified by the chemical reaction in solutions having various concentrations of a target molecule, both the position and intensity of the plasmon peak change in proportion to the concentration of the target molecule. We expect that the process developed in this work can be employed for fine tuning of the plasmon peak wavelength and also for the optical detection of various kinds of molecules. Moreover, this method may improve the measurement accuracy compared with existing approaches that use only one change (peak wavelength or peak intensity) as a readout value for the molecular detection.

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Identifying Differentially Expressed Genes and Small Molecule Drugs for Prostate Cancer by a Bioinformatics Strategy

  • Li, Jian;Xu, Ya-Hong;Lu, Yi;Ma, Xiao-Ping;Chen, Ping;Luo, Shun-Wen;Jia, Zhi-Gang;Liu, Yang;Guo, Yu
    • Asian Pacific Journal of Cancer Prevention
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    • v.14 no.9
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    • pp.5281-5286
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    • 2013
  • Purpose: Prostate cancer caused by the abnormal disorderly growth of prostatic acinar cells is the most prevalent cancer of men in western countries. We aimed to screen out differentially expressed genes (DEGs) and explore small molecule drugs for prostate cancer. Materials and Methods: The GSE3824 gene expression profile of prostate cancer was downloaded from Gene Expression Omnibus database which including 21 normal samples and 18 prostate cancer cells. The DEGs were identified by Limma package in R language and gene ontology and pathway enrichment analyses were performed. In addition, potential regulatory microRNAs and the target sites of the transcription factors were screened out based on the molecular signature database. In addition, the DEGs were mapped to the connectivity map database to identify potential small molecule drugs. Results: A total of 6,588 genes were filtered as DEGs between normal and prostate cancer samples. Examples such as ITGB6, ITGB3, ITGAV and ITGA2 may induce prostate cancer through actions on the focal adhesion pathway. Furthermore, the transcription factor, SP1, and its target genes ARHGAP26 and USF1 were identified. The most significant microRNA, MIR-506, was screened and found to regulate genes including ITGB1 and ITGB3. Additionally, small molecules MS-275, 8-azaguanine and pyrvinium were discovered to have the potential to repair the disordered metabolic pathways, abd furthermore to remedy prostate cancer. Conclusions: The results of our analysis bear on the mechanism of prostate cancer and allow screening for small molecular drugs for this cancer. The findings have the potential for future use in the clinic for treatment of prostate cancer.

Target Identification: A Challenging Step in Forward Chemical Genetics

  • Das, Raj Kumar;Samanta, Animesh;Ghosh, Krishnakanta;Zhai, Duanting;Xu, Wang;Su, Dongdong;Leong, Cheryl;Chang, Young-Tae
    • Interdisciplinary Bio Central
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    • v.3 no.1
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    • pp.3.1-3.16
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    • 2011
  • 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.

Structural and dynamic views of the CRISPR-Cas system at the single-molecule level

  • Lee, Seung Hwan;Bae, Sangsu
    • BMB Reports
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    • v.49 no.4
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    • pp.201-207
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    • 2016
  • The CRISPR-Cas system has emerged as a fascinating and important genome editing tool. It is now widely used in biology, biotechnology, and biomedical research in both academic and industrial settings. To improve the specificity and efficiency of Cas nucleases and to extend the applications of these systems for other areas of research, an understanding of their precise working mechanisms is crucial. In this review, we summarize current studies on the molecular structures and dynamic functions of type I and type II Cas nucleases, with a focus on target DNA searching and cleavage processes as revealed by single-molecule observations.

Combinatorial Library and Chemogenomics Approach: Discovery of Protein Secondary Structure Mimetic Small Molecule Inhibitors of Tryptase and Ref-l for Asthma

  • Moon, Sung-Hwan
    • Proceedings of the PSK Conference
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    • pp.92-92
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    • 2003
  • The drug discovery landscape is changing rapidly in the post-genomic era. Mapping of the human genome has led to an abundance of potential drug targets. Drug discovery times and costs can be significantly reduced by developing methods for high throughput target identification/ validation, multiplexed assay development and high efficient combinatorial chemistry. (omitted)

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