hERGscreen - Work Packages

 



          

WP1         Plant Selection

WP2         Virtual Access

WP3         Extraction, Isolation and Identification

WP4         In vitro hERG assessment

WP5         Pharmacokinetics and pharmacodynamics

WP6         Bioanalytics

WP7         Dissemination

WP8         Management


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hERGscreen_Tasse

Work Package 1: Plant Selection

Objectives

  • Bio-prospection for potentially harmful botanicals from South Africa, South America, and the Mediterranean area
  • Selection of potentially harmful botanicals containing relevant amounts of risky constituents
  • Supply of selected starting material

Description

The activities in WP1 include a preliminary selection of botanicals with high consumers’ relevance (herbal remedies, foodstuffs, nutritional supplements, spices) with potentially harmful effects in respect to the hERG channel. Emphasis will be put on botanicals available in and originating from the participating countries (South Africa, South America, Mediterranean area), where safety issues are of great importance.

Responsible Partner/s

P9 UFS

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hERGscreen_pharmacophore                  

Work Package 2: Virtual Access

Objectives

  • Rationalized access to potentially harmful botanicals through virtual prediction of putative hERG channel ligands
  • Insight into ligand-target interaction
  • Virtual ADMET profiling of selected hERG channel blockers

Description

The tasks in WP 2 consist of the application of computational strategies for rationalized, thus time- and cost saving approaches for the prediction of biological and physicochemical properties of constituents of botanicals in order to evaluate their potential cardiotoxic potential and their ADMET properties.

Responsible Partner/s

P1 UIBK

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hERGscreen_solvents

Work Package 3: Extraction, Isolation and Identification

Objectives

  • Extraction of the selected starting material
  • Profiling and micro-fractionation of hERG channel blocking extract
  • Isolation and identification of putative hERG-blockers

Description

Based on the rational selection of starting material (WP1, botanicals, preparations, plant species; ~100) the pharmacognostic partners of the consortium will be supplied with the selected materials and will proceed with their proper treatment in order to be extracted. The derived extracts will be screened in vitro on hERG interaction activity revealing potentially harmful botanicals. These will be further scrutinized for the isolation and identification of potential hERG blockers.

Responsible Partner/s

P2 NKUA, P8 UFSC

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hERGscreen_patch_clamp

Work Package 4: In vitro hERG assessment

Objectives

  • Screening of selected plant extracts for hERG channel inhibition
  • Testing of microfractions and establishing activity profiles of separated extracts
  • Establishing quantitative data on single compounds

Description

Selected plant extracts will be investigated with respect to hERG channel inhibition on hERG channels heterologoulsy expressed in Xenopus oocytes or mammalian cells. The mechanism of hERG channel block by identified NPs will be studied in more detail.

Responsible Partner/s

P3 UNIBAS, P5 UNIVie

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hERGscreen_QT hERGscreen_mouse

Work Package 5: Pharmacokinetics and pharmacodynamics (PK/PD)

Objectives

  • Rapid high throughput in vivo pharmacokinetic (PK) studies by measuring one PK parameter such as oral area under the curve (AUC) for a series of related compounds to expedite the selection of potential harmful hERG channel blockers
  • Assessment of the full plasma-concentration profile in rats after intravenous and oral dosing based on the selection of the previous objective, and evaluation of the relative bioavailability of compounds from corresponding extracts
  • In vivo assessment of hERG channel blockage by most potent in vitro hERG-blocking compounds using ECG measurements of the QT-interval in rats

Description

Pharmacokinetic and pharmacodynamics (PK/PD) concepts underlying drug disposition and response provide a quantitative framework with which to identify potential hERG channel blockers. Characterization of a compound’s PK is required to understand how dose level, route of administration, and dosing frequency are related to circulating drug levels and ultimately to concentrations in target tissues. An understanding of PD is required to describe the relationship between drug concentration at the site of action and pharmacologic activity. Thus, during the in vivo hERG screening, PK and PD of potential candidates are characterized in order to define the prospective toxic risks associated with their intake.

Responsible Partner/s

P4 BRFAA, P6 UF, P7 UFRGS

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hERGscreen_metabolomics

Work Package 6: Bioanalytics

Objectives

  • Pharmacokinetic profiling for compounds that are tested in vivo
  • Metabolic profiling from urine and plasma samples
  • Correlation of these data with biomarkers and PK/PD properties obtained in WP5

Description

Establishment of validated methodologies based on modern analytical approaches for the quantification of bioactive components of botanicals with hERG channel activity. The newly developed methods will be optimized and used for establishing the pharmacokinetic properties of those selected compounds following administration in rodents. In addition, bioanalytical methods (MS and NMR) will be established and applied towards the identification of potential biomarkers associated with the activity of hERG channel inhibitors. Finally, in an effort to further elucidate the mechanism of action of selected hERG channel inhibitors, their metabolism will be investigated based on in vitro incubations with rat and human liver microsomes. The major metabolites derived from those metabolic studies can be further evaluated in terms of hERG channel inhibitory potential.

Responsible Partner/s

P2 NKUA, P4 BRFAA, P6 UF, P7 UFRGS

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hERGscree_safety

Work Package 7: Dissemination

Objectives

  • Establishment of a scientific network in the field of cardiotoxic botanicals
  • Transfer of knowledge between partners
  • Promotion of the research activities of the consortium to the scientific community

Description

Transfer of knowledge to all scientists working in the field of NPs and other stakeholders in Europe and America and South-Africa will be achieved through the accomplishment of the hERG screen project by following an active dissemination and exploitation strategy.

Responsible Partner/s

P8 UFSC

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hERGscree_network

Work Package 8: Management

Objectives

  • Ensuring the effective coordination and collaboration of partners within the project
  • Fulfillment of project activities
  • Organization of the annual project meetings
  • Preparation and distribution of reports
  • Representation of the entire consortium towards the Commission

Description

The particular work package involves all the activities and procedures required for the administration of the project, communication between partners, organization of workshops and meetings.

Responsible Partner/s

P1 UIBK