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  1. Article ; Online: Contemporary strategies for the stabilization of peptides in the alpha-helical conformation.

    Henchey, Laura K / Jochim, Andrea L / Arora, Paramjit S

    Current opinion in chemical biology

    2008  Volume 12, Issue 6, Page(s) 692–697

    Abstract: Herein we review contemporary synthetic and protein design strategies to stabilize the alpha-helical motif in short peptides and miniature proteins. Advances in organometallic catalyst design, specifically for the olefin metathesis reaction, enable the ... ...

    Abstract Herein we review contemporary synthetic and protein design strategies to stabilize the alpha-helical motif in short peptides and miniature proteins. Advances in organometallic catalyst design, specifically for the olefin metathesis reaction, enable the use of hydrocarbon bridges to either crosslink side chains of specific residues or mimic intramolecular hydrogen bonds with carbon-carbon bonds. The resulting hydrocarbon-stapled and hydrogen bond surrogate alpha-helices provide unique synthetic ligands for targeting biomolecules. In the protein design realm, several classes of miniature proteins that display stable helical domains have been engineered and manipulated with powerful in vitro selection technologies to yield libraries of sequences that retain their helical folds. Rational re-design of these scaffolds provide distinctive reagents for the modulation of protein-protein interactions.
    MeSH term(s) Animals ; Cross-Linking Reagents/metabolism ; Hydrogen Bonding ; Models, Molecular ; Peptides/chemistry ; Peptides/metabolism ; Protein Stability ; Protein Structure, Secondary
    Chemical Substances Cross-Linking Reagents ; Peptides
    Language English
    Publishing date 2008-09-13
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1439176-4
    ISSN 1879-0402 ; 1367-5931
    ISSN (online) 1879-0402
    ISSN 1367-5931
    DOI 10.1016/j.cbpa.2008.08.019
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4986: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (2.OG)
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  2. Article ; Online: High specificity in protein recognition by hydrogen-bond-surrogate α-helices: selective inhibition of the p53/MDM2 complex.

    Henchey, Laura K / Porter, Jason R / Ghosh, Indraneel / Arora, Paramjit S

    Chembiochem : a European journal of chemical biology

    2010  Volume 11, Issue 15, Page(s) 2104–2107

    MeSH term(s) Amino Acid Sequence ; Circular Dichroism ; Crystallography, X-Ray ; Hydrogen Bonding ; Molecular Sequence Data ; Peptides/chemistry ; Peptidomimetics/chemistry ; Protein Binding ; Protein Structure, Secondary ; Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors ; Proto-Oncogene Proteins c-mdm2/metabolism ; Tumor Suppressor Protein p53/antagonists & inhibitors ; Tumor Suppressor Protein p53/metabolism
    Chemical Substances Peptides ; Peptidomimetics ; Tumor Suppressor Protein p53 ; MDM2 protein, human (EC 2.3.2.27) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
    Language English
    Publishing date 2010-09-06
    Publishing country Germany
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2020469-3
    ISSN 1439-7633 ; 1439-4227
    ISSN (online) 1439-7633
    ISSN 1439-4227
    DOI 10.1002/cbic.201000378
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  3. Article: High Specificity in Protein Recognition by Hydrogen-Bond-Surrogate α-Helices: Selective Inhibition of the p53/MDM2 Complex

    Henchey, Laura K / Porter, Jason R / Ghosh, Indraneel / Arora, Paramjit S

    Chembiochem. 2010 Oct. 18, v. 11, no. 15

    2010  

    Language English
    Dates of publication 2010-1018
    Size p. 2104-2107.
    Publishing place Wiley-VCH Verlag
    Document type Article
    ZDB-ID 2020469-3
    ISSN 1439-7633 ; 1439-4227
    ISSN (online) 1439-7633
    ISSN 1439-4227
    DOI 10.1002/cbic.201000378
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  4. Article ; Online: Adipocyte lipid synthesis coupled to neuronal control of thermogenic programming.

    Guilherme, Adilson / Pedersen, David J / Henchey, Elizabeth / Henriques, Felipe S / Danai, Laura V / Shen, Yuefei / Yenilmez, Batuhan / Jung, DaeYoung / Kim, Jason K / Lodhi, Irfan J / Semenkovich, Clay F / Czech, Michael P

    Molecular metabolism

    2017  Volume 6, Issue 8, Page(s) 781–796

    Abstract: Background: The de novo biosynthesis of fatty acids (DNL) through fatty acid synthase (FASN) in adipocytes is exquisitely regulated by nutrients, hormones, fasting, and obesity in mice and humans. However, the functions of DNL in adipocyte biology and ... ...

    Abstract Background: The de novo biosynthesis of fatty acids (DNL) through fatty acid synthase (FASN) in adipocytes is exquisitely regulated by nutrients, hormones, fasting, and obesity in mice and humans. However, the functions of DNL in adipocyte biology and in the regulation of systemic glucose homeostasis are not fully understood.
    Methods & results: Here we show adipocyte DNL controls crosstalk to localized sympathetic neurons that mediate expansion of beige/brite adipocytes within inguinal white adipose tissue (iWAT). Induced deletion of FASN in white and brown adipocytes of mature mice (iAdFASNKO mice) enhanced glucose tolerance, UCP1 expression, and cAMP signaling in iWAT. Consistent with induction of adipose sympathetic nerve activity, iAdFASNKO mice displayed markedly increased neuronal tyrosine hydroxylase (TH) and neuropeptide Y (NPY) content in iWAT. In contrast, brown adipose tissue (BAT) of iAdFASNKO mice showed no increase in TH or NPY, nor did FASN deletion selectively in brown adipocytes (UCP1-FASNKO mice) cause these effects in iWAT.
    Conclusions: These results demonstrate that downregulation of fatty acid synthesis via FASN depletion in white adipocytes of mature mice can stimulate neuronal signaling to control thermogenic programming in iWAT.
    MeSH term(s) Adipocytes/metabolism ; Animals ; Blood Glucose/metabolism ; Cells, Cultured ; Cyclic AMP/metabolism ; Fatty Acid Synthases/metabolism ; Fatty Acids/biosynthesis ; Lipogenesis ; Male ; Mice ; Mice, Inbred C57BL ; Neurons/metabolism ; Neurons/physiology ; Neuropeptide Y/metabolism ; Sympathetic Nervous System/cytology ; Sympathetic Nervous System/physiology ; Thermogenesis ; Tyrosine 3-Monooxygenase/metabolism ; Uncoupling Protein 1/metabolism
    Chemical Substances Blood Glucose ; Fatty Acids ; Neuropeptide Y ; Ucp1 protein, mouse ; Uncoupling Protein 1 ; Cyclic AMP (E0399OZS9N) ; Tyrosine 3-Monooxygenase (EC 1.14.16.2) ; Fatty Acid Synthases (EC 2.3.1.85)
    Language English
    Publishing date 2017-05-31
    Publishing country Germany
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 2212-8778
    ISSN (online) 2212-8778
    DOI 10.1016/j.molmet.2017.05.012
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Protein domain mimetics as in vivo modulators of hypoxia-inducible factor signaling.

    Kushal, Swati / Lao, Brooke Bullock / Henchey, Laura K / Dubey, Ramin / Mesallati, Hanah / Traaseth, Nathaniel J / Olenyuk, Bogdan Z / Arora, Paramjit S

    Proceedings of the National Academy of Sciences of the United States of America

    2013  Volume 110, Issue 39, Page(s) 15602–15607

    Abstract: Selective blockade of gene expression by designed small molecules is a fundamental challenge at the interface of chemistry, biology, and medicine. Transcription factors have been among the most elusive targets in genetics and drug discovery, but the ... ...

    Abstract Selective blockade of gene expression by designed small molecules is a fundamental challenge at the interface of chemistry, biology, and medicine. Transcription factors have been among the most elusive targets in genetics and drug discovery, but the fields of chemical biology and genetics have evolved to a point where this task can be addressed. Herein we report the design, synthesis, and in vivo efficacy evaluation of a protein domain mimetic targeting the interaction of the p300/CBP coactivator with the transcription factor hypoxia-inducible factor-1α. Our results indicate that disrupting this interaction results in a rapid down-regulation of hypoxia-inducible genes critical for cancer progression. The observed effects were compound-specific and dose-dependent. Gene expression profiling with oligonucleotide microarrays revealed effective inhibition of hypoxia-inducible genes with relatively minimal perturbation of nontargeted signaling pathways. We observed remarkable efficacy of the compound HBS 1 in suppressing tumor growth in the fully established murine xenograft models of renal cell carcinoma of the clear cell type. Our results suggest that rationally designed synthetic mimics of protein subdomains that target the transcription factor-coactivator interfaces represent a unique approach for in vivo modulation of oncogenic signaling and arresting tumor growth.
    MeSH term(s) Amino Acid Sequence ; Animals ; Antineoplastic Agents/pharmacology ; Cell Hypoxia ; Down-Regulation/drug effects ; Down-Regulation/genetics ; Female ; Gene Expression Profiling ; HeLa Cells ; Humans ; Hypoxia-Inducible Factor 1/chemistry ; Hypoxia-Inducible Factor 1/genetics ; Hypoxia-Inducible Factor 1/metabolism ; Ligands ; Mice ; Mice, Inbred BALB C ; Molecular Sequence Data ; Peptides/chemistry ; Peptides/pharmacology ; Protein Binding/drug effects ; Protein Multimerization ; Protein Stability/drug effects ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Response Elements/genetics ; Signal Transduction/drug effects ; Transcription, Genetic ; Vascular Endothelial Growth Factor A/metabolism ; Xenograft Model Antitumor Assays ; p300-CBP Transcription Factors/metabolism
    Chemical Substances Antineoplastic Agents ; Hypoxia-Inducible Factor 1 ; Ligands ; Peptides ; Vascular Endothelial Growth Factor A ; p300-CBP Transcription Factors (EC 2.3.1.48)
    Language English
    Publishing date 2013-09-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1312473110
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1148: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
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  6. Article ; Online: Inhibition of hypoxia inducible factor 1-transcription coactivator interaction by a hydrogen bond surrogate alpha-helix.

    Henchey, Laura K / Kushal, Swati / Dubey, Ramin / Chapman, Ross N / Olenyuk, Bogdan Z / Arora, Paramjit S

    Journal of the American Chemical Society

    2009  Volume 132, Issue 3, Page(s) 941–943

    Abstract: Designed ligands that inhibit hypoxia-inducible gene expression could offer new tools for genomic research and, potentially, drug discovery efforts for the treatment of neovascularization in cancers. We report a stabilized alpha-helix designed to target ... ...

    Abstract Designed ligands that inhibit hypoxia-inducible gene expression could offer new tools for genomic research and, potentially, drug discovery efforts for the treatment of neovascularization in cancers. We report a stabilized alpha-helix designed to target the binding interface between the C-terminal transactivation domain (C-TAD) of hypoxia-inducible factor 1alpha (HIF-1alpha) and cysteine-histidine rich region (CH1) of transcriptional coactivator CBP/p300. The synthetic helix disrupts the structure and function of this complex, resulting in a rapid downregulation of two hypoxia-inducible genes (VEGF and GLUT1) in cell culture.
    MeSH term(s) Cell Survival/drug effects ; Cells, Cultured ; Disulfides/pharmacology ; HeLa Cells ; Humans ; Hydrogen Bonding ; Hypoxia-Inducible Factor 1/antagonists & inhibitors ; Hypoxia-Inducible Factor 1/chemistry ; Hypoxia-Inducible Factor 1/metabolism ; Indole Alkaloids/pharmacology ; Protein Structure, Secondary ; Trans-Activators/antagonists & inhibitors ; Trans-Activators/chemistry ; Trans-Activators/metabolism
    Chemical Substances Disulfides ; Hypoxia-Inducible Factor 1 ; Indole Alkaloids ; Trans-Activators ; chetomin (1403-36-7)
    Language English
    Publishing date 2009-12-30
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 3155-0
    ISSN 1520-5126 ; 0002-7863
    ISSN (online) 1520-5126
    ISSN 0002-7863
    DOI 10.1021/ja9082864
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Bonn / Germany

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  7. Article ; Online: Adipocyte lipid synthesis coupled to neuronal control of thermogenic programming

    Adilson Guilherme / David J. Pedersen / Elizabeth Henchey / Felipe S. Henriques / Laura V. Danai / Yuefei Shen / Batuhan Yenilmez / DaeYoung Jung / Jason K. Kim / Irfan J. Lodhi / Clay F. Semenkovich / Michael P. Czech

    Molecular Metabolism, Vol 6, Iss 8, Pp 781-

    2017  Volume 796

    Abstract: Background: The de novo biosynthesis of fatty acids (DNL) through fatty acid synthase (FASN) in adipocytes is exquisitely regulated by nutrients, hormones, fasting, and obesity in mice and humans. However, the functions of DNL in adipocyte biology and in ...

    Abstract Background: The de novo biosynthesis of fatty acids (DNL) through fatty acid synthase (FASN) in adipocytes is exquisitely regulated by nutrients, hormones, fasting, and obesity in mice and humans. However, the functions of DNL in adipocyte biology and in the regulation of systemic glucose homeostasis are not fully understood. Methods & results: Here we show adipocyte DNL controls crosstalk to localized sympathetic neurons that mediate expansion of beige/brite adipocytes within inguinal white adipose tissue (iWAT). Induced deletion of FASN in white and brown adipocytes of mature mice (iAdFASNKO mice) enhanced glucose tolerance, UCP1 expression, and cAMP signaling in iWAT. Consistent with induction of adipose sympathetic nerve activity, iAdFASNKO mice displayed markedly increased neuronal tyrosine hydroxylase (TH) and neuropeptide Y (NPY) content in iWAT. In contrast, brown adipose tissue (BAT) of iAdFASNKO mice showed no increase in TH or NPY, nor did FASN deletion selectively in brown adipocytes (UCP1-FASNKO mice) cause these effects in iWAT. Conclusions: These results demonstrate that downregulation of fatty acid synthesis via FASN depletion in white adipocytes of mature mice can stimulate neuronal signaling to control thermogenic programming in iWAT.
    Keywords Adipocytes ; de novo lipogenesis ; iWAT browning ; Glucose homeostasis ; Sympathetic nerve activation ; Internal medicine ; RC31-1245
    Language English
    Publishing date 2017-08-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Direct inhibition of hypoxia-inducible transcription factor complex with designed dimeric epidithiodiketopiperazine.

    Block, Katherine M / Wang, Hui / Szabó, Lajos Z / Polaske, Nathan W / Henchey, Laura K / Dubey, Ramin / Kushal, Swati / László, Csaba F / Makhoul, Joshua / Song, Zuohe / Meuillet, Emmanuelle J / Olenyuk, Bogdan Z

    Journal of the American Chemical Society

    2009  Volume 131, Issue 50, Page(s) 18078–18088

    Abstract: Selective blockade of hypoxia-inducible gene expression by designed small molecules would prove valuable in suppressing tumor angiogenesis, metastasis and altered energy metabolism. We report the design, synthesis, and biological evaluation of a dimeric ... ...

    Abstract Selective blockade of hypoxia-inducible gene expression by designed small molecules would prove valuable in suppressing tumor angiogenesis, metastasis and altered energy metabolism. We report the design, synthesis, and biological evaluation of a dimeric epidithiodiketopiperazine (ETP) small molecule transcriptional antagonist targeting the interaction of the p300/CBP coactivator with the transcription factor HIF-1alpha. Our results indicate that disrupting this interaction results in rapid downregulation of hypoxia-inducible genes critical for cancer progression. The observed effects are compound-specific and dose-dependent. Controlling gene expression with designed small molecules targeting the transcription factor-coactivator interface may represent a new approach for arresting tumor growth.
    MeSH term(s) Angiogenesis Inhibitors/chemical synthesis ; Angiogenesis Inhibitors/chemistry ; Angiogenesis Inhibitors/pharmacology ; Angiogenesis Inhibitors/toxicity ; Binding, Competitive ; Cell Hypoxia ; Cell Line, Tumor ; Cell Survival/drug effects ; Diketopiperazines/chemical synthesis ; Diketopiperazines/chemistry ; Diketopiperazines/pharmacology ; Diketopiperazines/toxicity ; Disulfides/chemical synthesis ; Disulfides/chemistry ; Disulfides/pharmacology ; Disulfides/toxicity ; Dose-Response Relationship, Drug ; Gene Expression/drug effects ; Gene Expression Profiling ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Luciferases/genetics ; Models, Molecular ; Molecular Structure ; Neovascularization, Pathologic/metabolism ; Neovascularization, Pathologic/prevention & control ; Oligonucleotide Array Sequence Analysis ; Protein Binding ; Vascular Endothelial Growth Factor A/biosynthesis ; p300-CBP Transcription Factors/antagonists & inhibitors ; p300-CBP Transcription Factors/metabolism
    Chemical Substances Angiogenesis Inhibitors ; Diketopiperazines ; Disulfides ; HIF1A protein, human ; Hypoxia-Inducible Factor 1, alpha Subunit ; VEGFA protein, human ; Vascular Endothelial Growth Factor A ; Luciferases (EC 1.13.12.-) ; p300-CBP Transcription Factors (EC 2.3.1.48)
    Language English
    Publishing date 2009-12-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 3155-0
    ISSN 1520-5126 ; 0002-7863
    ISSN (online) 1520-5126
    ISSN 0002-7863
    DOI 10.1021/ja807601b
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Bonn / Germany

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