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Multidisciplinary European Joint Doctorate in the Design and Development of Glyco Drugs

Periodic Reporting for period 1 - PhD4GlycoDrug (Multidisciplinary European Joint Doctorate in the Design and Development of Glyco Drugs)

Reporting period: 2017-10-01 to 2019-09-30

Glycodrugs are drugs that interfere with protein-carbohydrate interactions, which are involved in many vital biological processes. Our understanding of these interactions is improving each year but so far, only a handful of registered drugs originate from the glycoscience area. This is undeniably connected with the specific challenges of design and syntheses of carbohydrate-based molecules, and most of the progress in this field, especially in the initial phases of the glycodrug discovery, has been made by European academic institutions such as those present in the PhD4Glycodrug consortium. Big pharmaceutical companies rarely see the opportunities for glycodrug development until academic institutions have paved the way. The expertise for glycodrug discovery already exists throughout Europe, but is rather dispersed in various academic institutions and small drug discovery enterprises. To bridge this gap and to create a large force in the glycodrug development, we have designed a joint PhD training and research programme that involves all phases of the glycodrug design and development pipeline preceding in vivo studies and clinical trials. We have brought together a multidisciplinary PhD4GlycoDrug Consortium consisting of participants from different sectors and disciplines involved in glycodrug discovery: six departments from universities across Europe with world-class medicinal chemists, organic chemists, biochemists and pharmacologists working in the glycosciences as scientists-in-charge of the PhD4GlycoDrug Consortium, five SMEs (PamGene, Acies Bio, SARomics, Elicityl and RedGlead) run by top-level researchers with strong track records in drug and glycodrug design and development, and a paramount research institute (CNRS) that, with the Glycopedia initiative (http://glycopedia.eu/) pioneers the dissemination of scientific information in glycoscience. Our consortium aims at the research level to make the compelling scientific point that glycodrugs can and need to be developed and at a human resource level that newly minted scientists from the project (12 ESRs) will make a difference and will pursue the glycodrug opportunities. The drug pipeline is covered from target identification to ADMET. The PhD4GlycoDrug Consortium will lead to a lasting innovative force in glycodrug discovery and continue to show big pharmaceutical companies its potential.
The present interim report covers the work performed within the first half of the PhD4GlycoDrug project period. The work is divided into 7 Work Packages and linked to the attached deliverables (WPs 1-7, according to the Grant Agreement):
• four scientific WPs (WP1-4) and attached deliverables (D1.1 – D1.4 D2.1 – D2.5 D3.1 – D3.4 D4.1 – D4.5)
• Training - WP5 and attached deliverables (D5.1 and D5.2)
• Communication and dissemination - WP6 and attached deliverables (D6.1 – D6.3) and
• Joint governing and management - WP7 and attached deliverables (D7.1 – D7.6).
The consortium achievements are reported in the deliverables’ reports and in the Technical Report Part B, so herein we report a brief summary.
Up till now, we have successfully performed the Kick-off meeting (D7.1) have signed and reported the Consortium Agreement (CA, D7.2) with Signed Administrative Agreements that Establish Joint/Double/Multiple PhDs (D7.3) and formed a Supervisory Board of the network (D7.4). We have furthermore successfully finished the Selection and Recruitment process (D7.5). On February 28 2018, the recruitment committee delivered the full list of ESRs to the supervisory board, and we have recruited 12 ESRs based on a transparent, fair and merit-based selection process. All ESRs have signed the employment contracts and were enrolled in the PhD programmes of the beneficiaries (2 per each PhD) to allow them to obtain double degrees. All of this was reported in the Mid-Term Progress Report (D7.6).
Communication to the general public as a part of the WP6 has been tackled by:
• Consortium webpage (D6.2 - Webpage with social media linking),
• Coordinator and Supervisory Board members presentations at local universities,
• Social media, and
• Researcher’s night.
Most of these actions were reported in the deliverable D6.1 - Report on Dissemination of the results to scientific audience. Apart from communication to the general public, all ESRs and some of the supervisory board members have reported their results on scientific conferences either by posters and/or lectures (Kanhaya Lal ESR2 was awarded the 1st prize the first prize in poster presentation at Glyco@Club days, Autrans, France).
The basis for the Training - WP5 was defined in the CA and the attached Administrative Agreement to Establish Joint/Double/Multiple PhDs. According to this, we have defined Individual Career Development Plans for each ESR (D5.1). Besides, a very detailed workshops/summer schools plan was defined (D5.2) and to date the PhD4GlycoDrug consortium has successfully organised and performed 5 training events in transferable skills and 5 summer schools/workshops. These training events and workshops are attached to the regular biannual consortium meetings.
The scientific WPs and attached deliverables under points D1.x D2.x D3.x and D4.x were reported in September 2018 (M12) and September 2019 (M24), but will also be reported continuously as new reports during months 36 and 48. Thus far, work has started on all macromolecular targets (Galectins, Siglecs, OGT, fungal lectins, bacterial sialic acid transporters), and the focus was on in silico methods for drug design (Structure- and Fragment-Based Drug Design, WP2), synthesis of carbohydrate-based ligands/inhibitors of selected targets (WP3), and biochemical and pharmacological evaluation of these compounds (WP4).
The progress beyond the state of the art is embedded in the PhD4GlycoDrug from its roots as it is (to the best of our knowledge) the only multidisciplinary EU-wide PhD programme that offers cutting-edge training-by-research in glycoscience with high quality supervision, transferable skills training, and workshops/summer schools. We will strive to set it as a common core standard for a glycodrug curriculum in the institutions involved, which could potentially become the seed of a common European training standard.
From a scientific perspective, PhD4GlycoDrug executes innovative research projects on specific macromolecular targets that bind and/or modify carbohydrate ligands involving all steps of early drug discovery from target identification and validation, through modern drug design and specific glyco-chemistry, to hit discovery and hit-to-lead development focusing on physico-chemical and ADMET properties. Some of the designed and synthesized compounds were proven to be potent ligands of the corresponding lectins and were co-crystalized in complex with proteins (6 synthesized ligands with Galectin-8, and α-methyl-fucoside with SapL1) to allow better understanding of their binding mode. 6 manuscripts are currently in the phase of preparation and will be submitted for publication in prominent scientific journals. The work done on several targets is currently being investigated for possible patent protection.
The first consortium meeting with all ESRs.
Consortium Kick-off meeting team in front of the University of Ljubljana building.
Consortium members at MAXIV Synchrotron