Chemical Modification and Organelle‐Specific Localization of Orlistat‐Like Natural‐Product‐Based Probes
Identifieur interne : 001675 ( Main/Exploration ); précédent : 001674; suivant : 001676Chemical Modification and Organelle‐Specific Localization of Orlistat‐Like Natural‐Product‐Based Probes
Auteurs : Peng-Yu Yang [Singapour] ; Kai Liu [Singapour] ; Chongjing Zhang [Singapour] ; Grace Y. J. Chen [Singapour] ; Yuan Shen [Singapour] ; Mun Hong Ngai [Singapour] ; Martin J. Lear [Singapour] ; Shao Q. Yao [Singapour]Source :
- Chemistry – An Asian Journal [ 1861-4728 ] ; 2011-10-04.
English descriptors
- Teeft :
- Affinity experiments, Affinity purification, Aliphatic, Aliphatic chain, Aliphatic chains, Amino, Amino ester, Amino ester moiety, Analogue, Analogue series, Angew, Assay, Benzylguanine orlistat variant, Biol, Biological screening, Calcd, Cdcl3, Cell line, Cellular, Cellular activities, Cellular activity, Cellular targets, Chem, Chemical modification, Chemical synthesis, Cleavable linker, Click, Click chemistry, Closer examination, Corresponding configurationally, Cytoplasm, Deionized water, Dmso, Drug delivery, Drug discovery, Effective concentration, Empai, Empai value, Empai values, Ester, Final concentration, Flash chromatography, Fluorescence scanning, Formic acid, Full papers, General mitsunobu reaction procedure, Generous gift, Gentle agitation, Gmbh, Green channels, Growth medium, Hepg2, Hepg2 cancer cells, Hepg2 cells, Histocompatibility antigen, Isoform, Johnsson, Kgaa, Lcm, Lcms analysis, Lipid, Mascot server, Mass analysis, Mitsunobu, Mitsunobu conditions, Mmol, Mobile phase, Modification, Negative control, Nucleus membrane, Organelle, Organic phase, Orlistat, Orlistat analogues, Orlistat probe, Orlistat probes, Orlistat structure, Overall workflow, Positive control, Pph3, Probe, Protein, Protein hits, Protein pellets, Proteome, Putative protein hits, Reaction mixture, Representative mitsunobu reaction procedure, Ribosomal protein, Room temperature, Science drive, Silica, Singapore, Stock solution, Subtle chemical modifications, Target identification, Terminal alkyne, Total number, Transient transfection, Trypsin digestion, Unique proteins, Unique targets, Verlag, Verlag gmbh, Vivo efficacy, Weinheim, Weinheim chem.
Abstract
Orlistat, also known as tetrahydrolipstatin (THL), is an FDA‐approved anti‐obesity drug with potential anti‐cancer activity. Previously, we developed a chemical proteomic approach, based on the Orlistat‐like probe (1a) for large‐scale identification of unknown cellular targets of Orlistat in human hepatocytes. In this article, we report the chemical synthesis and biological evaluation of an expanded set of Orlistat‐like compounds, with the intention to further dissect and manipulate potential cellular targets of Orlistat. In doing so, we carried out proteome‐wide activity‐based profiling and large‐scale pull‐down/LCMS analysis of these compounds in live HepG2 cells, and successfully identified many putative cellular targets for Orlistat and its structural analogues. By qualitatively assessing the spectra counts of potential protein hits against each of the seventeen Orlistat analogues, we obtained both common and unique targets of these probes. Our results revealed that subtle structural modifications of Orlistat led to noticeable changes in both the cellular potency and target profiles of the drug. In order to further improve the cellular activity of Orlistat, we successfully applied the well‐established AGT/SNAP‐tag technology to our cell‐permeable, benzylguanine (BG)‐containing Orlistat variant (4). We showed that the drug could be delivered and effectively retained in different sub‐cellular organelles of living cells. This strategy may provide a general and highly effective chemical tool for the potential sub‐cellular targeting of small molecule drugs.
The chemical synthesis and biological evaluation of an expanded set of Orlistat‐like compounds, and subsequent in situ proteome profiling and large‐scale pull‐down/LCMS analysis revealed many putative cellular targets (both common and unique) to these compounds in live HepG2 cells.
Url:
DOI: 10.1002/asia.201100306
Affiliations:
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Yao</name><affiliation wicri:level="4"><orgName type="university">Université nationale de Singapour</orgName><country>Singapour</country></affiliation><affiliation wicri:level="4"><country xml:lang="fr">Singapour</country><wicri:regionArea>Department of Biological Sciences, National University of Singapore, 14 Science Drive 4</wicri:regionArea><orgName type="university">Université nationale de Singapour</orgName></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Singapour</country></affiliation><affiliation wicri:level="4"><orgName type="university">Université nationale de Singapour</orgName><country>Singapour</country></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Chemistry – An Asian Journal</title><title level="j" type="sub">Celebrating the 10th Anniversary of Click Chemistry</title><title level="j" type="alt">CHEMISTRY AN ASIAN JOURNAL</title><idno type="ISSN">1861-4728</idno><idno type="eISSN">1861-471X</idno><imprint><biblScope unit="vol">6</biblScope><biblScope unit="issue">10</biblScope><biblScope unit="page" from="2762">2762</biblScope><biblScope unit="page" to="2775">2775</biblScope><biblScope unit="page-count">14</biblScope><publisher>WILEY‐VCH Verlag</publisher><pubPlace>Weinheim</pubPlace><date type="published" when="2011-10-04">2011-10-04</date></imprint><idno type="ISSN">1861-4728</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1861-4728</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="Teeft" xml:lang="en"><term>Affinity experiments</term><term>Affinity purification</term><term>Aliphatic</term><term>Aliphatic chain</term><term>Aliphatic chains</term><term>Amino</term><term>Amino ester</term><term>Amino ester moiety</term><term>Analogue</term><term>Analogue series</term><term>Angew</term><term>Assay</term><term>Benzylguanine orlistat variant</term><term>Biol</term><term>Biological screening</term><term>Calcd</term><term>Cdcl3</term><term>Cell line</term><term>Cellular</term><term>Cellular activities</term><term>Cellular activity</term><term>Cellular targets</term><term>Chem</term><term>Chemical modification</term><term>Chemical synthesis</term><term>Cleavable linker</term><term>Click</term><term>Click chemistry</term><term>Closer examination</term><term>Corresponding configurationally</term><term>Cytoplasm</term><term>Deionized water</term><term>Dmso</term><term>Drug delivery</term><term>Drug discovery</term><term>Effective concentration</term><term>Empai</term><term>Empai value</term><term>Empai values</term><term>Ester</term><term>Final concentration</term><term>Flash chromatography</term><term>Fluorescence scanning</term><term>Formic acid</term><term>Full papers</term><term>General mitsunobu reaction procedure</term><term>Generous gift</term><term>Gentle agitation</term><term>Gmbh</term><term>Green channels</term><term>Growth medium</term><term>Hepg2</term><term>Hepg2 cancer cells</term><term>Hepg2 cells</term><term>Histocompatibility antigen</term><term>Isoform</term><term>Johnsson</term><term>Kgaa</term><term>Lcm</term><term>Lcms analysis</term><term>Lipid</term><term>Mascot server</term><term>Mass analysis</term><term>Mitsunobu</term><term>Mitsunobu conditions</term><term>Mmol</term><term>Mobile phase</term><term>Modification</term><term>Negative control</term><term>Nucleus membrane</term><term>Organelle</term><term>Organic phase</term><term>Orlistat</term><term>Orlistat analogues</term><term>Orlistat probe</term><term>Orlistat probes</term><term>Orlistat structure</term><term>Overall workflow</term><term>Positive control</term><term>Pph3</term><term>Probe</term><term>Protein</term><term>Protein hits</term><term>Protein pellets</term><term>Proteome</term><term>Putative protein hits</term><term>Reaction mixture</term><term>Representative mitsunobu reaction procedure</term><term>Ribosomal protein</term><term>Room temperature</term><term>Science drive</term><term>Silica</term><term>Singapore</term><term>Stock solution</term><term>Subtle chemical modifications</term><term>Target identification</term><term>Terminal alkyne</term><term>Total number</term><term>Transient transfection</term><term>Trypsin digestion</term><term>Unique proteins</term><term>Unique targets</term><term>Verlag</term><term>Verlag gmbh</term><term>Vivo efficacy</term><term>Weinheim</term><term>Weinheim chem</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Orlistat, also known as tetrahydrolipstatin (THL), is an FDA‐approved anti‐obesity drug with potential anti‐cancer activity. Previously, we developed a chemical proteomic approach, based on the Orlistat‐like probe (1a) for large‐scale identification of unknown cellular targets of Orlistat in human hepatocytes. In this article, we report the chemical synthesis and biological evaluation of an expanded set of Orlistat‐like compounds, with the intention to further dissect and manipulate potential cellular targets of Orlistat. In doing so, we carried out proteome‐wide activity‐based profiling and large‐scale pull‐down/LCMS analysis of these compounds in live HepG2 cells, and successfully identified many putative cellular targets for Orlistat and its structural analogues. By qualitatively assessing the spectra counts of potential protein hits against each of the seventeen Orlistat analogues, we obtained both common and unique targets of these probes. Our results revealed that subtle structural modifications of Orlistat led to noticeable changes in both the cellular potency and target profiles of the drug. In order to further improve the cellular activity of Orlistat, we successfully applied the well‐established AGT/SNAP‐tag technology to our cell‐permeable, benzylguanine (BG)‐containing Orlistat variant (4). We showed that the drug could be delivered and effectively retained in different sub‐cellular organelles of living cells. This strategy may provide a general and highly effective chemical tool for the potential sub‐cellular targeting of small molecule drugs.</div><div type="abstract" xml:lang="en">The chemical synthesis and biological evaluation of an expanded set of Orlistat‐like compounds, and subsequent in situ proteome profiling and large‐scale pull‐down/LCMS analysis revealed many putative cellular targets (both common and unique) to these compounds in live HepG2 cells.</div></front></TEI><affiliations><list><country><li>Singapour</li></country><orgName><li>Université nationale de Singapour</li></orgName></list><tree><country name="Singapour"><noRegion><name sortKey="Yang, Peng U" sort="Yang, Peng U" uniqKey="Yang P" first="Peng-Yu" last="Yang">Peng-Yu Yang</name></noRegion><name sortKey="Chen, Grace Y J" sort="Chen, Grace Y J" uniqKey="Chen G" first="Grace Y. J." last="Chen">Grace Y. J. Chen</name><name sortKey="Chen, Grace Y J" sort="Chen, Grace Y J" uniqKey="Chen G" first="Grace Y. J." last="Chen">Grace Y. J. Chen</name><name sortKey="Lear, Martin J" sort="Lear, Martin J" uniqKey="Lear M" first="Martin J." last="Lear">Martin J. Lear</name><name sortKey="Liu, Kai" sort="Liu, Kai" uniqKey="Liu K" first="Kai" last="Liu">Kai Liu</name><name sortKey="Ngai, Mun Hong" sort="Ngai, Mun Hong" uniqKey="Ngai M" first="Mun Hong" last="Ngai">Mun Hong Ngai</name><name sortKey="Shen, Yuan" sort="Shen, Yuan" uniqKey="Shen Y" first="Yuan" last="Shen">Yuan Shen</name><name sortKey="Yao, Shao Q" sort="Yao, Shao Q" uniqKey="Yao S" first="Shao Q." last="Yao">Shao Q. Yao</name><name sortKey="Yao, Shao Q" sort="Yao, Shao Q" uniqKey="Yao S" first="Shao Q." last="Yao">Shao Q. Yao</name><name sortKey="Yao, Shao Q" sort="Yao, Shao Q" uniqKey="Yao S" first="Shao Q." last="Yao">Shao Q. Yao</name><name sortKey="Yao, Shao Q" sort="Yao, Shao Q" uniqKey="Yao S" first="Shao Q." last="Yao">Shao Q. Yao</name><name sortKey="Zhang, Chongjing" sort="Zhang, Chongjing" uniqKey="Zhang C" first="Chongjing" last="Zhang">Chongjing Zhang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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