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  1. Article ; Online: Design of functionalised circular tandem repeat proteins with longer repeat topologies and enhanced subunit contact surfaces.

    Hallinan, Jazmine P / Doyle, Lindsey A / Shen, Betty W / Gewe, Mesfin M / Takushi, Brittany / Kennedy, Madison A / Friend, Della / Roberts, James M / Bradley, Philip / Stoddard, Barry L

    Communications biology

    2021  Volume 4, Issue 1, Page(s) 1240

    Abstract: Circular tandem repeat proteins ('cTRPs') are de novo designed protein scaffolds (in this and prior studies, based on antiparallel two-helix bundles) that contain repeated protein sequences and structural motifs and form closed circular structures. They ... ...

    Abstract Circular tandem repeat proteins ('cTRPs') are de novo designed protein scaffolds (in this and prior studies, based on antiparallel two-helix bundles) that contain repeated protein sequences and structural motifs and form closed circular structures. They can display significant stability and solubility, a wide range of sizes, and are useful as protein display particles for biotechnology applications. However, cTRPs also demonstrate inefficient self-assembly from smaller subunits. In this study, we describe a new generation of cTRPs, with longer repeats and increased interaction surfaces, which enhanced the self-assembly of two significantly different sizes of homotrimeric constructs. Finally, we demonstrated functionalization of these constructs with (1) a hexameric array of peptide-binding SH2 domains, and (2) a trimeric array of anti-SARS CoV-2 VHH domains. The latter proved capable of sub-nanomolar binding affinities towards the viral receptor binding domain and potent viral neutralization function.
    MeSH term(s) Amino Acid Sequence ; Angiotensin-Converting Enzyme 2/metabolism ; COVID-19/metabolism ; COVID-19/virology ; Computer Simulation ; Crystallization ; HEK293 Cells ; Humans ; Models, Molecular ; Neutralization Tests ; Protein Binding ; Protein Domains ; Protein Engineering/methods ; Protein Folding ; Protein Structure, Secondary ; Proteins/chemistry ; Proteins/metabolism ; SARS-CoV-2/metabolism ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/metabolism ; Tandem Repeat Sequences
    Chemical Substances Proteins ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
    Language English
    Publishing date 2021-10-29
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2399-3642
    ISSN (online) 2399-3642
    DOI 10.1038/s42003-021-02766-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Ex silico engineering of cystine-dense peptides yielding a potent bispecific T cell engager.

    Crook, Zachary R / Girard, Emily J / Sevilla, Gregory P / Brusniak, Mi-Youn / Rupert, Peter B / Friend, Della J / Gewe, Mesfin M / Clarke, Midori / Lin, Ida / Ruff, Raymond / Pakiam, Fiona / Phi, Tinh-Doan / Bandaranayake, Ashok / Correnti, Colin E / Mhyre, Andrew J / Nairn, Natalie W / Strong, Roland K / Olson, James M

    Science translational medicine

    2022  Volume 14, Issue 645, Page(s) eabn0402

    Abstract: Cystine-dense peptides (CDPs) are a miniprotein class that can drug difficult targets with high affinity and low immunogenicity. Tools for their design, however, are not as developed as those for small-molecule and antibody drugs. CDPs have diverse ... ...

    Abstract Cystine-dense peptides (CDPs) are a miniprotein class that can drug difficult targets with high affinity and low immunogenicity. Tools for their design, however, are not as developed as those for small-molecule and antibody drugs. CDPs have diverse taxonomic origins, but structural characterization is lacking. Here, we adapted Iterative Threading ASSEmbly Refinement (I-TASSER) and Rosetta protein modeling software for structural prediction of 4298 CDP scaffolds and performed in silico prescreening for CDP binders to targets of interest. Mammalian display screening of a library of docking-enriched, methionine and tyrosine scanned (DEMYS) CDPs against PD-L1 yielded binders from four distinct CDP scaffolds. One was affinity-matured, and cocrystallography yielded a high-affinity (
    MeSH term(s) Animals ; Humans ; Mice ; Antibodies, Bispecific/pharmacology ; Antibodies, Bispecific/therapeutic use ; B7-H1 Antigen ; CD3 Complex ; Cystine ; Disease Models, Animal ; Mammals ; Peptides ; T-Lymphocytes
    Chemical Substances Antibodies, Bispecific ; B7-H1 Antigen ; CD3 Complex ; Cystine (48TCX9A1VT) ; Peptides
    Language English
    Publishing date 2022-05-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2518854-9
    ISSN 1946-6242 ; 1946-6234
    ISSN (online) 1946-6242
    ISSN 1946-6234
    DOI 10.1126/scitranslmed.abn0402
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Control of Tumor Initiation by NKG2D Naturally Expressed on Ovarian Cancer Cells.

    Cai, Xin / Caballero-Benitez, Andrea / Gewe, Mesfin M / Jenkins, Isaac C / Drescher, Charles W / Strong, Roland K / Spies, Thomas / Groh, Veronika

    Neoplasia (New York, N.Y.)

    2017  Volume 19, Issue 6, Page(s) 471–482

    Abstract: Cancer cells may co-opt the NKG2D lymphocyte receptor to complement the presence of its ligands for autonomous stimulation of oncogenic signaling. Previous studies raise the possibility that cancer cell NKG2D may induce high malignancy traits, but its ... ...

    Abstract Cancer cells may co-opt the NKG2D lymphocyte receptor to complement the presence of its ligands for autonomous stimulation of oncogenic signaling. Previous studies raise the possibility that cancer cell NKG2D may induce high malignancy traits, but its full oncogenic impact is unknown. Using epithelial ovarian cancer as model setting, we show here that ex vivo NKG2D
    Language English
    Publishing date 2017-06
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1483840-0
    ISSN 1476-5586 ; 1522-8002
    ISSN (online) 1476-5586
    ISSN 1522-8002
    DOI 10.1016/j.neo.2017.03.005
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: A potent peptide-steroid conjugate accumulates in cartilage and reverses arthritis without evidence of systemic corticosteroid exposure.

    Cook Sangar, Michelle L / Girard, Emily J / Hopping, Gene / Yin, Chunfeng / Pakiam, Fiona / Brusniak, Mi-Youn / Nguyen, Elizabeth / Ruff, Raymond / Gewe, Mesfin M / Byrnes-Blake, Kelly / Nairn, Natalie W / Miller, Dennis M / Mehlin, Christopher / Strand, Andrew D / Mhyre, Andrew J / Correnti, Colin E / Strong, Roland K / Simon, Julian A / Olson, James M

    Science translational medicine

    2020  Volume 12, Issue 533

    Abstract: On-target, off-tissue toxicity limits the systemic use of drugs that would otherwise reduce symptoms or reverse the damage of arthritic diseases, leaving millions of patients in pain and with limited physical mobility. We identified cystine-dense ... ...

    Abstract On-target, off-tissue toxicity limits the systemic use of drugs that would otherwise reduce symptoms or reverse the damage of arthritic diseases, leaving millions of patients in pain and with limited physical mobility. We identified cystine-dense peptides (CDPs) that rapidly accumulate in cartilage of the knees, ankles, hips, shoulders, and intervertebral discs after systemic administration. These CDPs could be used to concentrate arthritis drugs in joints. A cartilage-accumulating peptide, CDP-11R, reached peak concentration in cartilage within 30 min after administration and remained detectable for more than 4 days. Structural analysis of the peptides by crystallography revealed that the distribution of positive charge may be a distinguishing feature of joint-accumulating CDPs. In addition, quantitative whole-body autoradiography showed that the disulfide-bonded tertiary structure is critical for cartilage accumulation and retention. CDP-11R distributed to joints while carrying a fluorophore imaging agent or one of two different steroid payloads, dexamethasone (dex) and triamcinolone acetonide (TAA). Of the two payloads, the dex conjugate did not advance because the free drug released into circulation was sufficient to cause on-target toxicity. In contrast, the CDP-11R-TAA conjugate alleviated joint inflammation in the rat collagen-induced model of rheumatoid arthritis while avoiding toxicities that occurred with nontargeted steroid treatment at the same molar dose. This conjugate shows promise for clinical development and establishes proof of concept for multijoint targeting of disease-modifying therapeutic payloads.
    MeSH term(s) Adrenal Cortex Hormones ; Animals ; Arthritis, Experimental/drug therapy ; Cartilage ; Humans ; Peptides ; Rats ; Steroids
    Chemical Substances Adrenal Cortex Hormones ; Peptides ; Steroids
    Language English
    Publishing date 2020-03-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2518854-9
    ISSN 1946-6242 ; 1946-6234
    ISSN (online) 1946-6242
    ISSN 1946-6234
    DOI 10.1126/scitranslmed.aay1041
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Detection and activation of HIV broadly neutralizing antibody precursor B cells using anti-idiotypes.

    Bancroft, Tara / DeBuysscher, Blair L / Weidle, Connor / Schwartz, Allison / Wall, Abigail / Gray, Matthew D / Feng, Junli / Steach, Holly R / Fitzpatrick, Kristin S / Gewe, Mesfin M / Skog, Patrick D / Doyle-Cooper, Colleen / Ota, Takayuki / Strong, Roland K / Nemazee, David / Pancera, Marie / Stamatatos, Leonidas / McGuire, Andrew T / Taylor, Justin J

    The Journal of experimental medicine

    2019  Volume 216, Issue 10, Page(s) 2331–2347

    Abstract: Many tested vaccines fail to provide protection against disease despite the induction of antibodies that bind the pathogen of interest. In light of this, there is much interest in rationally designed subunit vaccines that direct the antibody response to ... ...

    Abstract Many tested vaccines fail to provide protection against disease despite the induction of antibodies that bind the pathogen of interest. In light of this, there is much interest in rationally designed subunit vaccines that direct the antibody response to protective epitopes. Here, we produced a panel of anti-idiotype antibodies able to specifically recognize the inferred germline version of the human immunodeficiency virus 1 (HIV-1) broadly neutralizing antibody b12 (iglb12). We determined the crystal structure of two anti-idiotypes in complex with iglb12 and used these anti-idiotypes to identify rare naive human B cells expressing B cell receptors with similarity to iglb12. Immunization with a multimerized version of this anti-idiotype induced the proliferation of transgenic murine B cells expressing the iglb12 heavy chain in vivo, despite the presence of deletion and anergy within this population. Together, our data indicate that anti-idiotypes are a valuable tool for the study and induction of potentially protective antibodies.
    MeSH term(s) Adult ; Animals ; Antibodies, Anti-Idiotypic/immunology ; Antibodies, Neutralizing/immunology ; Female ; HIV Antibodies/immunology ; HIV Infections/genetics ; HIV Infections/immunology ; HIV-1/genetics ; HIV-1/immunology ; Humans ; Male ; Mice ; Mice, Transgenic ; Precursor Cells, B-Lymphoid/immunology
    Chemical Substances Antibodies, Anti-Idiotypic ; Antibodies, Neutralizing ; HIV Antibodies
    Keywords covid19
    Language English
    Publishing date 2019-07-25
    Publishing country United States
    Document type Clinical Trial ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20190164
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    Ua VI Zs.107: Show issues Location:
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  6. Article: Anti-CD28 Antibody-Initiated Cytokine Storm in Canines.

    Rosinski, Steven L / Storb, Rainer / Strong, Roland K / Sale, George E / Stone, Diane M / Gewe, Mesfin M / Friend, Della J / Abrams, V Kraig / Randolph-Habecker, Julie / Graves, Scott S

    Transplantation direct

    2015  Volume 1, Issue 2

    Abstract: Background: CD28 signal blockade following T cell receptor activation is under intense investigation as a tolerance-inducing therapy for transplantation. Our goal is to produce a CD28-specific reagent as a therapy for the prevention of graft rejection ... ...

    Abstract Background: CD28 signal blockade following T cell receptor activation is under intense investigation as a tolerance-inducing therapy for transplantation. Our goal is to produce a CD28-specific reagent as a therapy for the prevention of graft rejection and graft-versus-host disease in the canine model of allogeneic hematopoietic cell transplantation (HCT).
    Methods: We infused a monoclonal mouse anti-canine CD28 antibody (1C6 mAb) into four dogs and a fragment of antigen-binding (1C6 Fab) into two dogs. Pharmacokinetics, pathology, cytokine release, and the crystal structure of 1C6 Fv were evaluated.
    Results: Within an hour of an IV injection of the 1C6 mAb, the dogs became leukopenic and developed a steroid-refractory cytokine storm. Two of the dogs developed high fevers, one experienced diffuse alveolar hemorrhage, and another developed gastrointestinal hemorrhage. The cytokine storm was characterized by elevated plasma levels of MCP-1, IP-10, IL-10, IL-6, and TNF-α. In addition, one dog showed elevated levels of IL-2, IL-8, and IL-18. In contrast, infusion of 1C6 Fab was well tolerated without any side effects. Dry-coating 1C6 mAb onto tissue culture plates induced CD3-independent proliferation and TNF-alpha production. Crystal structure analysis revealed that 1C6 binds to canine CD28 in a manner different than previously reported for conventional agonistic or superagonistic antibodies.
    Conclusions: These results indicate that dogs and humans develop a similar cytokine storm following infusion ofanti-CD28 mAb, providing an appropriate large animal for further study. 1C6 Fab warrants evaluation as a tolerance-inducing reagent in the canine model of allogeneic HCT.
    Language English
    Publishing date 2015-04-28
    Publishing country United States
    Document type Journal Article
    ISSN 2373-8731
    ISSN 2373-8731
    DOI 10.1097/TXD.0000000000000516
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Screening, large-scale production and structure-based classification of cystine-dense peptides.

    Correnti, Colin E / Gewe, Mesfin M / Mehlin, Christopher / Bandaranayake, Ashok D / Johnsen, William A / Rupert, Peter B / Brusniak, Mi-Youn / Clarke, Midori / Burke, Skyler E / De Van Der Schueren, Willem / Pilat, Kristina / Turnbaugh, Shanon M / May, Damon / Watson, Alex / Chan, Man Kid / Bahl, Christopher D / Olson, James M / Strong, Roland K

    Nature structural & molecular biology

    2018  Volume 25, Issue 3, Page(s) 270–278

    Abstract: Peptides folded through interwoven disulfides display extreme biochemical properties and unique medicinal potential. However, their exploitation has been hampered by the limited amounts isolatable from natural sources and the expense of chemical ... ...

    Abstract Peptides folded through interwoven disulfides display extreme biochemical properties and unique medicinal potential. However, their exploitation has been hampered by the limited amounts isolatable from natural sources and the expense of chemical synthesis. We developed reliable biological methods for high-throughput expression, screening and large-scale production of these peptides: 46 were successfully produced in multimilligram quantities, and >600 more were deemed expressible through stringent screening criteria. Many showed extreme resistance to temperature, proteolysis and/or reduction, and all displayed inhibitory activity against at least 1 of 20 ion channels tested, thus confirming their biological functionality. Crystal structures of 12 confirmed proper cystine topology and the utility of crystallography to study these molecules but also highlighted the need for rational classification. Previous categorization attempts have focused on limited subsets featuring distinct motifs. Here we present a global definition, classification and analysis of >700 structures of cystine-dense peptides, providing a unifying framework for these molecules.
    MeSH term(s) Amino Acid Sequence ; Crystallography, X-Ray ; Cystine/chemistry ; HEK293 Cells ; Humans ; Ion Channels/antagonists & inhibitors ; Models, Molecular ; Peptide Biosynthesis ; Peptides/chemistry ; Peptides/classification ; Peptides/pharmacology
    Chemical Substances Ion Channels ; Peptides ; Cystine (48TCX9A1VT)
    Language English
    Publishing date 2018-02-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2126708-X
    ISSN 1545-9985 ; 1545-9993
    ISSN (online) 1545-9985
    ISSN 1545-9993
    DOI 10.1038/s41594-018-0033-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.MG 56: Show issues

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