Periodic Reporting for period 2 - REsolution (Add medical genetic solutions to RESOLUTE (REsolution))
Période du rapport: 2022-06-01 au 2023-12-31
Nutrients like vitamins, sugars, and amino acids enter our cells through transporter proteins on the cell surface. Solute carriers (SLCs) are the largest class of transporter proteins in the human genome with more than 400 members. They play a crucial role in maintaining cellular well-being and mediating the uptake of nutrients as well as medicines. SLCs are associated with numerous human diseases, including cancer, neurological and metabolic disorders, and almost half of the members with Mendelian diseases. The REsolution project focuses on understanding how genetic variants of SLCs are linked to human diseases, a critical step in developing effective medicines targeting these proteins.
To achieve this goal, the REsolution project compiled information on the entire class of SLCs, creating a central database to assess their association with human diseases. Next, REsolution selected several SLCs involved in disease for experimental studies. Through the generation of biological tools, deep mutational scanning (DMS) datasets, transport assays, and experimental characterization of disease-related variants, REsolution provided a key toolkit for future drug discovery for these targets.
Our key achievements include:
• Over 200 plasmids and cell lines were generated for SLC genetic variants involved in human diseases. These reagents enabled the molecular characterization of disease mutants.
• Deep mutational scanning (DMS) datasets were acquired for SLC13A5, SLC19A1, and SLC2A1, providing valuable insights into the impact of all possible genetic variation in respective SLCs (manuscripts in preparation).
• Transport assays were developed to assess disease-related variants of various SLCs. This enabled the investigation of whether and how disease mutants impact the SLC’s transport function.
• Experimental characterization of SLC single variants for several targets (SLC6A8 published in Ferrada et al., J Mol Biol, 2024; SLC1A3 published in Gorostiola González, M., Sijben, H., et al., Front. Mol. Biosci., 2023 and several manuscripts in preparation). These studies provide in-depth analyses of disease mutants and contribute to a better understanding of respective diseases.
• A structural analysis on the entire SLC family of transporters was performed using experimental, homology and AlphaFold2 predictions-based structural databases (Ferrada & Superti-Furga iScience 2022). This improves our understanding of structural similarity between SLCs and supports the interpretation of genetic variation.
The project's results are disseminated through the SLC Knowledgebase (https://re-solute.eu/knowledgebase) as well as a web portal (https://re-solute.eu/resolution) offering interactive tools like the genetic scoreboard, compendium, and phenotypes dashboards. Scientific publications, conference presentations, and workshops, including those during the Final RESOLUTE conference “Unlocking Transporter for Drug Discovery” (talks available at https://re-solute.eu/conference) amplified the global visibility of SLCs in human diseases. In general, the project's commitment to open-access and knowledge dissemination, evident through the mentioned resources and activities, ensured that the broader scientific and medical communities are equipped with the latest insights. This collaborative approach fosters a collective understanding of SLCs' significance in human diseases and may catalyze further research on this class of proteins.
Our key achievements include:
• Over 200 plasmids and cell lines were generated for SLC genetic variants involved in human diseases. These reagents enabled the molecular characterization of disease mutants.
• Deep mutational scanning (DMS) datasets were acquired for SLC13A5, SLC19A1, and SLC2A1, providing valuable insights into the impact of all possible genetic variation in respective SLCs (manuscripts in preparation).
• Transport assays were developed to assess disease-related variants of various SLCs. This enabled the investigation of whether and how disease mutants impact the SLC’s transport function.
• Experimental characterization of SLC single variants for several targets (SLC6A8 published in Ferrada et al., J Mol Biol, 2024; SLC1A3 published in Gorostiola González, M., Sijben, H., et al., Front. Mol. Biosci., 2023 and several manuscripts in preparation). These studies provide in-depth analyses of disease mutants and contribute to a better understanding of respective diseases.
• A structural analysis on the entire SLC family of transporters was performed using experimental, homology and AlphaFold2 predictions-based structural databases (Ferrada & Superti-Furga iScience 2022). This improves our understanding of structural similarity between SLCs and supports the interpretation of genetic variation.
The project's results are disseminated through the SLC Knowledgebase (https://re-solute.eu/knowledgebase) as well as a web portal (https://re-solute.eu/resolution) offering interactive tools like the genetic scoreboard, compendium, and phenotypes dashboards. Scientific publications, conference presentations, and workshops, including those during the Final RESOLUTE conference “Unlocking Transporter for Drug Discovery” (talks available at https://re-solute.eu/conference) amplified the global visibility of SLCs in human diseases. In general, the project's commitment to open-access and knowledge dissemination, evident through the mentioned resources and activities, ensured that the broader scientific and medical communities are equipped with the latest insights. This collaborative approach fosters a collective understanding of SLCs' significance in human diseases and may catalyze further research on this class of proteins.
The impact of the REsolution extends beyond the project, offering implications for human health and drug development. By combining computational and experimental approaches, the unique database created by REsolution could acts as a “compass” for the medical and scientific communities, facilitating the identification of the most feasible SLCs involved in human diseases for drug discovery campaigns. REsolution can also provide an important resource for SLC rare disease consortia. As genetically validated targets have a higher probability of success in the clinics, the effort to functionally elucidate the impact of such coding mutations will enable a deeper mechanistic understanding and more targeted lead finding.