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  1. AU="Guernieri, Rebecca L"
  2. AU="Xing, Z Y"
  3. AU="Yu-Heng Cheng"
  4. AU=Freeman Richard B Jr
  5. AU="Wang, Qi-En"
  6. AU="Mallamaci, M"
  7. AU="Turk, Yael R"
  8. AU="Tinto, Monica"
  9. AU="Selvendiran, Karuppaiyah" AU="Selvendiran, Karuppaiyah"
  10. AU="Enns, Murray W"
  11. AU="Yaohua Yang" AU="Yaohua Yang"

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  1. Artikel ; Online: Potency and stability of a trivalent, catalytically inactive vaccine against botulinum neurotoxin serotypes C, E and F (triCEF).

    Webb, Robert / Wright, Patrick M / Brown, Jennifer L / Skerry, Janet C / Guernieri, Rebecca L / Smith, Theresa J / Stawicki, Christopher / Smith, Leonard A

    Toxicon : official journal of the International Society on Toxinology

    2020  Band 176, Seite(n) 67–76

    Abstract: Botulism is an acute neuroparalytic affliction of the motor and autonomic neurons caused by the toxins produced from Clostridium botulinum and related bacterial strains. The botulinum neurotoxins, or BoNTs, consist of a phylogenetically diverse group of ... ...

    Abstract Botulism is an acute neuroparalytic affliction of the motor and autonomic neurons caused by the toxins produced from Clostridium botulinum and related bacterial strains. The botulinum neurotoxins, or BoNTs, consist of a phylogenetically diverse group of highly potent protein toxins. Current medical interventions for confirmed cases of botulism are limited to immediate administration of antitoxins and respiratory support. There is currently no licensed vaccine against botulism in the United States. The most widely distributed botulism vaccine was a pentavalent BoNT toxoid (PBT) against serotypes A-E administered until 2011 under an investigational new drug license. A binary vaccine composed of the recombinant, non-toxic, receptor binding domains (RBD) of serotypes/A1 and/B1 has completed a phase II clinical trial, but has yet to attain full licensure. We have previously published data demonstrating catalytically inactive, full length botulinum neurotoxin holoproteins (ciBoNT HPs) against serotypes/A1,/B1,/C1,/E1 and/F1 provide equivalent or superior potency against parental and dissimilar subtype toxins as compared the RBD vaccines. Here we describe the consistent potencies of the three independent lots each of ciBoNT/C1,/E1, and/F1 HPs against substantial monovalent challenges of the parental toxins. We also present data that a trivalent formulation of ciBoNT/C1,/E1 and/F1 (triCEF) maintains potency against both monovalent and polyvalent toxin challenges when stored as an adjuvanted vaccine at 4-8 °C for up to 2 years.
    Mesh-Begriff(e) Animals ; Antitoxins/chemistry ; Antitoxins/pharmacology ; Botulinum Toxins/toxicity ; Humans ; United States ; Vaccines, Synthetic/immunology
    Chemische Substanzen Antitoxins ; Vaccines, Synthetic ; Botulinum Toxins (EC 3.4.24.69)
    Sprache Englisch
    Erscheinungsdatum 2020-02-04
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 204479-1
    ISSN 1879-3150 ; 0041-0101
    ISSN (online) 1879-3150
    ISSN 0041-0101
    DOI 10.1016/j.toxicon.2020.02.001
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Recombinant Botulinum Neurotoxin Hc Subunit (BoNT Hc) and Catalytically Inactive Clostridium botulinum Holoproteins (ciBoNT HPs) as Vaccine Candidates for the Prevention of Botulism.

    Webb, Robert P / Smith, Theresa J / Smith, Leonard A / Wright, Patrick M / Guernieri, Rebecca L / Brown, Jennifer L / Skerry, Janet C

    Toxins

    2017  Band 9, Heft 9

    Abstract: There are few available medical countermeasures against botulism and the discontinuation of the pentavalent botulinum toxoid vaccine by the Centers for Disease Control and Prevention in 2011 has resulted in the need for a safe and effective prophylactic ... ...

    Abstract There are few available medical countermeasures against botulism and the discontinuation of the pentavalent botulinum toxoid vaccine by the Centers for Disease Control and Prevention in 2011 has resulted in the need for a safe and effective prophylactic alternative. Advances in genetic engineering have resulted in subsequent vaccine efforts being primarily focused on the production of highly purified recombinant protein antigens representing one or more domains of the botulinum neurotoxin. Recombinant subunit vaccines based on the carboxy one-third of the toxin (Hc) developed in our lab against serotypes A-F have been shown to be safe and effective. However, in response to the identification of an ever increasing number of BoNT subtypes with significant amino acid heterogeneity, we have developed catalytically inactive BoNT holoproteins (ciBoNT HPs) in an attempt to elicit greater protective immunity to address these toxin variants. Here we report the production of ciBoNT/B1 HP, ciBoNT/C1 HP, ciBoNT/E1 HP and ciBoNT/F1 HP and compare the immunological and protective abilities of ciBoNT HPs and BoNT/A Hc, BoNT/B Hc, BoNT/C Hc, BoNT/E Hc and BoNT/F Hc vaccines when challenged with homologous and heterologous toxins. Our results suggest the ciBoNT HP vaccines exhibit superior potency after single vaccinations but multiple vaccinations with BoNT/Hc antigens resulted in increased survival rates at the toxin challenge levels used.
    Mesh-Begriff(e) Amino Acid Sequence ; Animals ; Bacterial Proteins/immunology ; Bacterial Vaccines/chemistry ; Bacterial Vaccines/pharmacology ; Botulinum Toxins/immunology ; Botulism/prevention & control ; Clostridium botulinum ; Mice ; Recombinant Proteins/immunology ; Vaccines, Subunit/chemistry ; Vaccines, Subunit/pharmacology ; Vaccines, Synthetic/chemistry ; Vaccines, Synthetic/pharmacology
    Chemische Substanzen Bacterial Proteins ; Bacterial Vaccines ; Recombinant Proteins ; Vaccines, Subunit ; Vaccines, Synthetic ; Botulinum Toxins (EC 3.4.24.69)
    Sprache Englisch
    Erscheinungsdatum 2017--03
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2518395-3
    ISSN 2072-6651 ; 2072-6651
    ISSN (online) 2072-6651
    ISSN 2072-6651
    DOI 10.3390/toxins9090269
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: Utilizing Ayurvedic literature for the identification of novel phytochemical inhibitors of botulinum neurotoxin A.

    Yalamanchili, Chinni / Manda, Vamshi K / Chittiboyina, Amar G / Guernieri, Rebecca L / Harrell, William A / Webb, Robert P / Smith, Leonard A / Khan, Ikhlas A

    Journal of ethnopharmacology

    2017  Band 197, Seite(n) 211–217

    Abstract: Ethnopharmacological relevance: Ayurveda, an ancient holistic system of health care practiced on the Indian subcontinent, utilizes a number of multi-plant formulations and is considered by many as a potential source for novel treatments, as well as the ... ...

    Abstract Ethnopharmacological relevance: Ayurveda, an ancient holistic system of health care practiced on the Indian subcontinent, utilizes a number of multi-plant formulations and is considered by many as a potential source for novel treatments, as well as the identification of new drugs. Our aim is to identify novel phytochemicals for the inhibition of bacterial exotoxin, botulinum neurotoxin A (BoNT/A) based on Ayurvedic literature. BoNT/A is released by Clostridium species, which when ingested, inhibits the release of acetylcholine by concentrating at the neuromuscular junction and causes flaccid paralysis, resulting in a condition termed as botulism, and may also lead to death due to respiratory arrest.
    Methods: Fifteen plants were selected from the book 'Diagnosis and treatment of diseases in Ayurveda' by Vaidya Bhagwan Dash and Lalitesh Kashyap, based on their frequency of use in the formulations used for the treatment of six diseases with neuromuscular symptoms similar to botulism. Phytochemicals from these plants were screened using in silico, and in vitro methods. Structures of 570 reported phytochemicals from 14 plants were docked inside six reported BoNT/A light chain crystal structures using ensemble docking module in Maestro (Schrödinger, LLE).
    Results: From the docking scores and structural diversity, nine compounds including acoric acid 1, three flavonoids, three coumarins derivatives, one kava lactone were selected and screened using an in vitro HPLC-based protease assay. The bioassay results showed that several compounds possess BoNT/A LC inhibition of 50-60% when compared to positive controls NSC 84094 and CB7967495 (80-95%).
    Conclusion: Further testing of the active compounds identified from Ayurvedic literature and structure-activity studies of acoric acid 1 using more sensitive bioassays is under way. The identification of acoric acid 1, a novel scaffold against BoNT/A, exemplifies the utility of Ayurvedic literature for the discovery of novel drug leads.
    Mesh-Begriff(e) Botulinum Toxins, Type A/antagonists & inhibitors ; Coumarins/chemistry ; Coumarins/pharmacology ; Cyclohexanones/chemistry ; Cyclohexanones/pharmacology ; Ethnopharmacology/methods ; Flavonoids/chemistry ; Flavonoids/pharmacology ; Kava/chemistry ; Lactones/chemistry ; Lactones/pharmacology ; Medicine, Ayurvedic ; Phytochemicals/chemistry ; Phytochemicals/pharmacology
    Chemische Substanzen Coumarins ; Cyclohexanones ; Flavonoids ; Lactones ; Phytochemicals ; acoric acid (65WVB6DB6D) ; Botulinum Toxins, Type A (EC 3.4.24.69)
    Sprache Englisch
    Erscheinungsdatum 2017-02-02
    Erscheinungsland Ireland
    Dokumenttyp Journal Article
    ZDB-ID 134511-4
    ISSN 1872-7573 ; 0378-8741
    ISSN (online) 1872-7573
    ISSN 0378-8741
    DOI 10.1016/j.jep.2016.07.069
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel: Utilizing Ayurvedic literature for the identification of novel phytochemical inhibitors of botulinum neurotoxin A

    Yalamanchili, Chinni / Chittiboyina, Amar G / Guernieri, Rebecca L / Harrell, William A / Khan, Ikhlas A / Manda, Vamshi K / Smith, Leonard A / Webb, Robert P

    Elsevier Ireland Ltd. Journal of ethnopharmacology. 2017 Feb. 02, v. 197

    2017  

    Abstract: Ayurveda, an ancient holistic system of health care practiced on the Indian subcontinent, utilizes a number of multi-plant formulations and is considered by many as a potential source for novel treatments, as well as the identification of new drugs. Our ... ...

    Abstract Ayurveda, an ancient holistic system of health care practiced on the Indian subcontinent, utilizes a number of multi-plant formulations and is considered by many as a potential source for novel treatments, as well as the identification of new drugs. Our aim is to identify novel phytochemicals for the inhibition of bacterial exotoxin, botulinum neurotoxin A (BoNT/A) based on Ayurvedic literature. BoNT/A is released by Clostridium species, which when ingested, inhibits the release of acetylcholine by concentrating at the neuromuscular junction and causes flaccid paralysis, resulting in a condition termed as botulism, and may also lead to death due to respiratory arrest.Fifteen plants were selected from the book ‘Diagnosis and treatment of diseases in Ayurveda’ by Vaidya Bhagwan Dash and Lalitesh Kashyap, based on their frequency of use in the formulations used for the treatment of six diseases with neuromuscular symptoms similar to botulism. Phytochemicals from these plants were screened using in silico, and in vitro methods. Structures of 570 reported phytochemicals from 14 plants were docked inside six reported BoNT/A light chain crystal structures using ensemble docking module in Maestro (Schrödinger, LLE).From the docking scores and structural diversity, nine compounds including acoric acid 1, three flavonoids, three coumarins derivatives, one kava lactone were selected and screened using an in vitro HPLC-based protease assay. The bioassay results showed that several compounds possess BoNT/A LC inhibition of 50–60% when compared to positive controls NSC 84094 and CB7967495 (80–95%).Further testing of the active compounds identified from Ayurvedic literature and structure-activity studies of acoric acid 1 using more sensitive bioassays is under way. The identification of acoric acid 1, a novel scaffold against BoNT/A, exemplifies the utility of Ayurvedic literature for the discovery of novel drug leads.
    Schlagwörter acetylcholine ; active ingredients ; Ayurvedic medicine ; bioassays ; botulinum toxin ; botulism ; Clostridium ; coumarins ; crystal structure ; death ; exotoxins ; flavonoids ; health services ; in vitro studies ; kava ; new drugs ; paralysis ; proteinases ; synapse ; India
    Sprache Englisch
    Erscheinungsverlauf 2017-0202
    Umfang p. 211-217.
    Erscheinungsort Elsevier B.V.
    Dokumenttyp Artikel
    ZDB-ID 134511-4
    ISSN 1872-7573 ; 0378-8741
    ISSN (online) 1872-7573
    ISSN 0378-8741
    DOI 10.1016/j.jep.2016.07.069
    Datenquelle NAL Katalog (AGRICOLA)

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