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Article ; Online: Attenuated diphtheria toxin mediates siRNA delivery.

Arnold, Amy E / Smith, Laura J / Beilhartz, Greg L / Bahlmann, Laura C / Jameson, Emma / Melnyk, Roman A / Shoichet, Molly S

Science advances

2020 Volume 6, Issue 18

Abstract: Toxins efficiently deliver cargo to cells by binding to cell surface ligands, initiating endocytosis, and escaping the endolysosomal pathway into the cytoplasm. We took advantage of this delivery pathway by conjugating an attenuated diphtheria toxin to ... ...

Abstract	Toxins efficiently deliver cargo to cells by binding to cell surface ligands, initiating endocytosis, and escaping the endolysosomal pathway into the cytoplasm. We took advantage of this delivery pathway by conjugating an attenuated diphtheria toxin to siRNA, thereby achieving gene downregulation in patient-derived glioblastoma cells. We delivered siRNA against integrin-β1 (
MeSH term(s)	Diphtheria Toxin/genetics ; Diphtheria Toxin/metabolism ; Endocytosis ; Endosomes/metabolism ; Humans ; Lysosomes/metabolism ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism
Chemical Substances	Diphtheria Toxin ; RNA, Small Interfering
Language	English
Publishing date	2020-05-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.aaz4848
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Article ; Online: Small Molecules Take A Big Step Against Clostridium difficile.

Beilhartz, Greg L / Tam, John / Melnyk, Roman A

Trends in microbiology

2015 Volume 23, Issue 12, Page(s) 746–748

Abstract: Effective treatment of Clostridium difficile infections demands a shift away from antibiotics towards toxin-neutralizing agents. Work by Bender et al., using a drug that attenuates toxin action in vivo without affecting bacterial survival, demonstrates ... ...

Abstract	Effective treatment of Clostridium difficile infections demands a shift away from antibiotics towards toxin-neutralizing agents. Work by Bender et al., using a drug that attenuates toxin action in vivo without affecting bacterial survival, demonstrates the exciting potential of small molecules as a new modality in the fight against C. difficile.
MeSH term(s)	Animals ; Anti-Bacterial Agents/therapeutic use ; Clostridium Infections/drug therapy ; Clostridium difficile/isolation & purification ; Virulence/drug effects
Chemical Substances	Anti-Bacterial Agents
Language	English
Publishing date	2015-12
Publishing country	England
Document type	Comment ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1158963-2
ISSN	1878-4380 ; 0966-842X
ISSN (online)	1878-4380
ISSN	0966-842X
DOI	10.1016/j.tim.2015.10.009
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Zs.A 3738: Show issues

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Article ; Online: Repurposing bacterial toxins for intracellular delivery of therapeutic proteins.

Beilhartz, Greg L / Sugiman-Marangos, Seiji N / Melnyk, Roman A

Biochemical pharmacology

2017 Volume 142, Page(s) 13–20

Abstract: Despite enormous efforts, achieving efficacious levels of proteins inside mammalian cells remains one of the greatest challenges in biologics-based drug discovery and development. The inability of proteins to readily cross biological membranes precludes ... ...

Abstract	Despite enormous efforts, achieving efficacious levels of proteins inside mammalian cells remains one of the greatest challenges in biologics-based drug discovery and development. The inability of proteins to readily cross biological membranes precludes access to the wealth of intracellular targets and applications that lie within mammalian cells. Existing methods of delivery commonly suffer from an inability to target specific cells and tissues, poor endosomal escape, and limited in vivo efficacy. The aim of the present commentary is to highlight the potential of certain classes of bacterial toxins, which naturally deliver a large protein into the cytosolic compartment of target cells after binding a host cell-surface receptor with high affinity, as robust protein delivery platforms. We review the progress made in recent years toward demonstrating the utility of these systems at delivering a wide variety of protein cargo, with special attention paid to three distinct toxin-based platforms. We contend that with recent advances in protein deimmunization strategies, bacterial toxins are poised to introduce biologics into the inner sanctum of cells and treat a wealth of heretofore untreatable diseases with a new generation of therapeutics.
MeSH term(s)	Animals ; Bacterial Toxins/chemistry ; Bacterial Toxins/metabolism ; Cytosol/metabolism ; Drug Carriers/chemistry ; Drug Carriers/metabolism ; Drug Discovery/methods ; Drug Discovery/trends ; Humans ; Pharmaceutical Preparations/administration & dosage ; Pharmaceutical Preparations/metabolism ; Protein Binding ; Receptors, Cell Surface/metabolism ; Recombinant Proteins/administration & dosage ; Recombinant Proteins/metabolism
Chemical Substances	Bacterial Toxins ; Drug Carriers ; Pharmaceutical Preparations ; Receptors, Cell Surface ; Recombinant Proteins
Language	English
Publishing date	2017-10-15
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/j.bcp.2017.04.009
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Zs.A 19: Show issues

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Article ; Online: Comment on "A small-molecule antivirulence agent for treating Clostridium difficile infection".

Beilhartz, Greg L / Tam, John / Zhang, Zhifen / Melnyk, Roman A

Science translational medicine

2016 Volume 8, Issue 370, Page(s) 370tc2

Abstract: New insights into the mechanism of action of ebselen, a small-molecule antivirulence agent that reduces disease pathology in a mouse model of Clostridium difficile infection, suggest a different molecular target may be responsible for its efficacy. ...

Abstract	New insights into the mechanism of action of ebselen, a small-molecule antivirulence agent that reduces disease pathology in a mouse model of Clostridium difficile infection, suggest a different molecular target may be responsible for its efficacy.
MeSH term(s)	Animals ; Anti-Bacterial Agents ; Clostridium Infections ; Clostridium difficile ; Mice
Chemical Substances	Anti-Bacterial Agents
Language	English
Publishing date	2016-12-18
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.aad8926
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Zs.A 6941: Show issues

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Article: Small Molecules Take A Big Step Against Clostridium difficile

Beilhartz, Greg L / John Tam / Roman A. Melnyk

Trends in microbiology. 2015 Dec., v. 23

2015

Abstract	Effective treatment of Clostridium difficile infections demands a shift away from antibiotics towards toxin-neutralizing agents. Work by Bender et al., using a drug that attenuates toxin action in vivo without affecting bacterial survival, demonstrates the exciting potential of small molecules as a new modality in the fight against C. difficile.
Keywords	antibiotics ; Clostridium difficile ; drugs
Language	English
Dates of publication	2015-12
Size	p. 746-748.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1158963-2
ISSN	1878-4380 ; 0966-842X
ISSN (online)	1878-4380
ISSN	0966-842X
DOI	10.1016/j.tim.2015.10.009
Database	NAL-Catalogue (AGRICOLA)

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Z 2005/714: Show issues

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Article ; Online: An engineered chimeric toxin that cleaves activated mutant and wild-type RAS inhibits tumor growth.

Vidimar, Vania / Beilhartz, Greg L / Park, Minyoung / Biancucci, Marco / Kieffer, Matthew B / Gius, David R / Melnyk, Roman A / Satchell, Karla J F

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

2020 Volume 117, Issue 29, Page(s) 16938–16948

Abstract: Despite nearly four decades of effort, broad inhibition of oncogenic RAS using small-molecule approaches has proven to be a major challenge. Here we describe the development of a pan-RAS biologic inhibitor composed of the RAS-RAP1-specific endopeptidase ... ...

Abstract	Despite nearly four decades of effort, broad inhibition of oncogenic RAS using small-molecule approaches has proven to be a major challenge. Here we describe the development of a pan-RAS biologic inhibitor composed of the RAS-RAP1-specific endopeptidase fused to the protein delivery machinery of diphtheria toxin. We show that this engineered chimeric toxin irreversibly cleaves and inactivates intracellular RAS at low picomolar concentrations terminating downstream signaling in receptor-bearing cells. Furthermore, we demonstrate in vivo target engagement and reduction of tumor burden in three mouse xenograft models driven by either wild-type or mutant
MeSH term(s)	Animals ; Antineoplastic Agents/therapeutic use ; Cells, Cultured ; Diphtheria Toxin/chemistry ; Diphtheria Toxin/genetics ; Diphtheria Toxin/metabolism ; Endopeptidases/chemistry ; Endopeptidases/genetics ; Endopeptidases/metabolism ; Female ; HCT116 Cells ; Humans ; Male ; Mice ; Mice, Nude ; Mutation ; Neoplasms, Experimental/drug therapy ; Protein Sorting Signals ; Proteolysis ; Recombinant Proteins/therapeutic use ; rap1 GTP-Binding Proteins/metabolism ; ras Proteins/genetics ; ras Proteins/metabolism
Chemical Substances	Antineoplastic Agents ; Diphtheria Toxin ; Protein Sorting Signals ; Recombinant Proteins ; Endopeptidases (EC 3.4.-) ; Rap1 protein, mouse (EC 3.6.5.2) ; rap1 GTP-Binding Proteins (EC 3.6.5.2) ; ras Proteins (EC 3.6.5.2)
Language	English
Publishing date	2020-07-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2000312117
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Zs.A 1148: Show issues

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Article ; Online: A designer peptide against the EAG2-Kvβ2 potassium channel targets the interaction of cancer cells and neurons to treat glioblastoma.

Nature cancer

2023 Volume 4, Issue 10, Page(s) 1418–1436

Abstract: Glioblastoma (GBM) is an incurable brain cancer that lacks effective therapies. Here we show that EAG2 and Kvβ2, which are predominantly expressed by GBM cells at the tumor-brain interface, physically interact to form a potassium channel complex due to a ...

Abstract	Glioblastoma (GBM) is an incurable brain cancer that lacks effective therapies. Here we show that EAG2 and Kvβ2, which are predominantly expressed by GBM cells at the tumor-brain interface, physically interact to form a potassium channel complex due to a GBM-enriched Kvβ2 isoform. In GBM cells, EAG2 localizes at neuron-contacting regions in a Kvβ2-dependent manner. Genetic knockdown of the EAG2-Kvβ2 complex decreases calcium transients of GBM cells, suppresses tumor growth and invasion and extends the survival of tumor-bearing mice. We engineered a designer peptide to disrupt EAG2-Kvβ2 interaction, thereby mitigating tumor growth in patient-derived xenograft and syngeneic mouse models across GBM subtypes without overt toxicity. Neurons upregulate chemoresistant genes in GBM cells in an EAG2-Kvβ2-dependent manner. The designer peptide targets neuron-associated GBM cells and possesses robust efficacy in treating temozolomide-resistant GBM. Our findings may lead to the next-generation therapeutic agent to benefit patients with GBM.
MeSH term(s)	Humans ; Mice ; Animals ; Glioblastoma/drug therapy ; Temozolomide/pharmacology ; Temozolomide/therapeutic use ; Ether-A-Go-Go Potassium Channels/therapeutic use ; Disease Models, Animal ; Peptides/therapeutic use ; Neurons/pathology
Chemical Substances	Temozolomide (YF1K15M17Y) ; Ether-A-Go-Go Potassium Channels ; Peptides
Language	English
Publishing date	2023-09-11
Publishing country	England
Document type	Journal Article
ISSN	2662-1347
ISSN (online)	2662-1347
DOI	10.1038/s43018-023-00626-8
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Article ; Online: HIV-1 Ribonuclease H: Structure, Catalytic Mechanism and Inhibitors.

Beilhartz, Greg L / Götte, Matthias

Viruses

2010 Volume 2, Issue 4, Page(s) 900–926

Abstract: Since the human immunodeficiency virus (HIV) was discovered as the etiological agent of acquired immunodeficiency syndrome (AIDS), it has encouraged much research into antiviral compounds. The reverse transcriptase (RT) of HIV has been a main target for ... ...

Abstract	Since the human immunodeficiency virus (HIV) was discovered as the etiological agent of acquired immunodeficiency syndrome (AIDS), it has encouraged much research into antiviral compounds. The reverse transcriptase (RT) of HIV has been a main target for antiviral drugs. However, all drugs developed so far inhibit the polymerase function of the enzyme, while none of the approved antiviral agents inhibit specifically the necessary ribonuclease H (RNase H) function of RT. This review provides a background on structure-function relationships of HIV-1 RNase H, as well as an outline of current attempts to develop novel, potent chemotherapeutics against a difficult drug target.
Language	English
Publishing date	2010-03-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v2040900
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Article ; Online: Recognition of Semaphorin Proteins by P. sordellii Lethal Toxin Reveals Principles of Receptor Specificity in Clostridial Toxins.

Lee, Hunsang / Beilhartz, Greg L / Kucharska, Iga / Raman, Swetha / Cui, Hong / Lam, Mandy Hiu Yi / Liang, Huazhu / Rubinstein, John L / Schramek, Daniel / Julien, Jean-Philippe / Melnyk, Roman A / Taipale, Mikko

Cell

2020 Volume 182, Issue 2, Page(s) 345–356.e16

Abstract: Pathogenic clostridial species secrete potent toxins that induce severe host tissue damage. Paeniclostridium sordellii lethal toxin (TcsL) causes an almost invariably lethal toxic shock syndrome associated with gynecological infections. TcsL is 87% ... ...

Abstract	Pathogenic clostridial species secrete potent toxins that induce severe host tissue damage. Paeniclostridium sordellii lethal toxin (TcsL) causes an almost invariably lethal toxic shock syndrome associated with gynecological infections. TcsL is 87% similar to C. difficile TcdB, which enters host cells via Frizzled receptors in colon epithelium. However, P. sordellii infections target vascular endothelium, suggesting that TcsL exploits another receptor. Here, using CRISPR/Cas9 screening, we establish semaphorins SEMA6A and SEMA6B as TcsL receptors. We demonstrate that recombinant SEMA6A can protect mice from TcsL-induced edema. A 3.3 Å cryo-EM structure shows that TcsL binds SEMA6A with the same region that in TcdB binds structurally unrelated Frizzled. Remarkably, 15 mutations in this evolutionarily divergent surface are sufficient to switch binding specificity of TcsL to that of TcdB. Our findings establish semaphorins as physiologically relevant receptors for TcsL and reveal the molecular basis for the difference in tissue targeting and disease pathogenesis between highly related toxins.
MeSH term(s)	Animals ; Bacterial Toxins/chemistry ; Bacterial Toxins/metabolism ; Bacterial Toxins/toxicity ; Binding Sites ; CRISPR-Cas Systems/genetics ; Cell Line ; Clostridium sordellii/metabolism ; Cryoelectron Microscopy ; Edema/pathology ; Edema/prevention & control ; Female ; Humans ; Lung/drug effects ; Lung/pathology ; Mice ; Mice, Inbred C57BL ; Molecular Dynamics Simulation ; Mutagenesis, Site-Directed ; Protein Binding ; Protein Structure, Tertiary ; Recombinant Proteins/biosynthesis ; Recombinant Proteins/isolation & purification ; Recombinant Proteins/therapeutic use ; Semaphorins/chemistry ; Semaphorins/genetics ; Semaphorins/metabolism
Chemical Substances	Bacterial Toxins ; Recombinant Proteins ; Sema6a protein, mouse ; Sema6b protein, mouse ; Semaphorins
Keywords	covid19
Language	English
Publishing date	2020-06-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2020.06.005
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Zs.A 1167: 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) ab Jg. 2022: Lesesaal (EG)
Zs.MG 58: Show issues

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Article ; Online: Exploiting the diphtheria toxin internalization receptor enhances delivery of proteins to lysosomes for enzyme replacement therapy.

Sugiman-Marangos, Seiji N / Beilhartz, Greg L / Zhao, Xiaochu / Zhou, Dongxia / Hua, Rong / Kim, Peter K / Rini, James M / Minassian, Berge A / Melnyk, Roman A

Science advances

2020 Volume 6, Issue 50

Abstract: Enzyme replacement therapy, in which a functional copy of an enzyme is injected either systemically or directly into the brain of affected individuals, has proven to be an effective strategy for treating certain lysosomal storage diseases. The ... ...

Abstract	Enzyme replacement therapy, in which a functional copy of an enzyme is injected either systemically or directly into the brain of affected individuals, has proven to be an effective strategy for treating certain lysosomal storage diseases. The inefficient uptake of recombinant enzymes via the mannose-6-phosphate receptor, however, prohibits the broad utility of replacement therapy. Here, to improve the efficiency and efficacy of lysosomal enzyme uptake, we exploited the strategy used by diphtheria toxin to enter into the endolysosomal network of cells by creating a chimera between the receptor-binding fragment of diphtheria toxin and the lysosomal hydrolase TPP1. We show that chimeric TPP1 binds with high affinity to target cells and is efficiently delivered into lysosomes. Further, we show superior uptake of chimeric TPP1 over TPP1 alone in brain tissue following intracerebroventricular injection in mice lacking TPP1, demonstrating the potential of this strategy for enhancing lysosomal storage disease therapy.
MeSH term(s)	Animals ; Brain/metabolism ; Diphtheria Toxin/metabolism ; Diphtheria Toxin/pharmacology ; Enzyme Replacement Therapy ; Lysosomes/metabolism ; Mice ; Receptor, IGF Type 2/genetics ; Receptor, IGF Type 2/metabolism ; Recombinant Proteins/metabolism
Chemical Substances	Diphtheria Toxin ; Receptor, IGF Type 2 ; Recombinant Proteins
Language	English
Publishing date	2020-12-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abb0385
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