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

Project Information

PhD4GlycoDrug

Grant agreement ID: 765581

DOI

10.3030/765581

Project closed

EC signature date 17 August 2017

Start date 1 October 2017

End date 31 January 2022

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 3 080 389,68

EU contribution

€ 3 080 389,68

Coordinated by

UNIVERZA V LJUBLJANI
Slovenia

Periodic Reporting for period 2 - PhD4GlycoDrug (Multidisciplinary European Joint Doctorate in the Design and Development of Glyco Drugs)

Reporting period: 2019-10-01 to 2022-01-31

Summary of the context and overall objectives of the project

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. 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 (UL, UU, UMIL, ULUND, UNIBAS and UGA) 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 research institute (CNRS) that pioneers the dissemination of scientific information in glycoscience with the Glycopedia initiative (http://glycopedia.eu/). PhD4GlycoDrug was a European Joint Doctorate, so accordingly the Consortium’s overarching aim was to establish a glycodrug discovery research and training platform that:
• to the best of our knowledge is currently not present in Europe,
• will start and perform innovative research projects on specific macromolecular targets that bind and/or modify carbohydrate ligands, involving all steps of early drug discovery,
• incorporates methodologies of modern drug design, target identification and validation, hit discovery, hit-to-lead and lead development focusing on physico-chemical and ADMET properties,
• uses specific glycochemistry tailored to glycodrug discovery specific needs, e.g. synthesis of metabolically stable glycosides, glycomimetics, multivalent glycodrugs and glycochips,
• will nourish basic glycoscience steps that are not covered by big pharmaceutical companies, and will allow big pharma to cherry-pick the most successful results,
• will join all individual research projects in a uniform training and research program across the network that covers the drug discovery pipeline from target identification to ADMET, as delineated in the Work Package list,
• will allow building a solid foundation for long-term European excellence in glycodrug discovery, also supported by the involvement of four European SMEs already active in the sector,
• will outlive the present project and allow a sustainable environment for the training of competent young researchers that will fuel future glycodrug discovery processes.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The work of the PhD4GlycoDrug Consortium was divided into 7 Work Packages:
• four scientific WPs (WP1-4),
• Training - WP5,
• Communication and dissemination - WP6, and
• Joint governing and management - WP7.
Within the PhD4GlycoDrug, the drug pipeline was covered from target identification to ADMET, and has led to interesting innovations in the discovery of molecular probes and lead compounds aimed to target the next macromolecular targets: fucose and mannose specific lectins from lung pathogens and opportunistic fungi, like BC2L-C and SapL-1; Siglec family of receptors with the emphasis on Siglec-8; Galectins family of galactose-recognising lectins with the emphasis on galectin-8; O-GlcNAc transferase (OGT), and Bacterial transport proteins - membrane-bound sialic acid sodium solute symporter.
Groups at UMIL and UGA have managed to obtain first-in-class ligands for pathogenic lectins BC2L-C and SapL-1 that were co-crystallized with the native proteins and represent an excellent springboard for future structure-based drug design campaigns. Efforts from partners from UNIBAS and UL have resulted in a library of first selective Siglec-8 ligands. Joint efforts of ULUND and UL yielded selective and potent inhibitors of galectin-8 N and several of these inhibitors were co-crystallized in partnership with SARomics. An important breakthrough has been achieved on galectin-3, where low nanomolar inhibitors are currently in the phase of in vivo assays for assessing their immunomodulatory activity. Work done at UL and UU resulted in probably the most potent nanomolar OGT inhibitors that are currently being developed as first in vivo active molecular probes for target validation. Crystallization hits have been obtained by ULUND and UNIBAS for the sialic acid transporters. The above results were published in 17 original papers (for complete list please visit https://www.phd4glycodrug.eu/) but many more manuscripts are in the pipeline. Furthermore, the results were communicated to the scientific public in many symposia, while communication to the general public has been tackled by Consortium webpage, Coordinator and Supervisory Board members presentations at local universities, social media, and Researcher’s night.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The progress beyond the state of the art is embedded in the PhD4GlycoDrug from its roots as it was (to the best of our knowledge) the only multidisciplinary EU-wide PhD programme that offered cutting-edge training-by-research in glycoscience with high quality supervision, transferable skills training, and workshops/summer schools. We have shaped 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 executed 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 to allow better understanding of their binding mode and future structure-based drug design. The work done on several targets is currently being investigated for possible patent protection.
Our consortium aimed 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 during and after the end of the project. 6 ESRs have already defended their PhD theses, while 6 are just now finishing their PhD research work. It is our great pleasure that 5 out of 6 ESRs that have concluded their PhD continue to pursue their career in the broader field of drug discovery and glycoscience in both academia and industry.

The first consortium meeting with all ESRs.

Final meeting of the consortium in Ljubljana.

Consortium Kick-off meeting team in front of the University of Ljubljana building.

Consortium members at MAXIV Synchrotron