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Projeto de investigação
European Joint Programme on Rare Diseases
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Publicações
Computational Approaches Drive Developments in Immune-Oncology Therapies for PD-1/PD-L1 Immune Checkpoint Inhibitors
Publication . Sobral, Patrícia S.; Luz, Vanessa C. C.; Almeida, João M. G. C. F.; Videira, Paula A.; Pereira, Florbela; DQ - Departamento de Química; LAQV@REQUIMTE; UCIBIO - Applied Molecular Biosciences Unit; DCV - Departamento de Ciências da Vida; MDPI - Multidisciplinary Digital Publishing Institute
Computational approaches in immune-oncology therapies focus on using data-driven methods to identify potential immune targets and develop novel drug candidates. In particular, the search for PD-1/PD-L1 immune checkpoint inhibitors (ICIs) has enlivened the field, leveraging the use of cheminformatics and bioinformatics tools to analyze large datasets of molecules, gene expression and protein–protein interactions. Up to now, there is still an unmet clinical need for improved ICIs and reliable predictive biomarkers. In this review, we highlight the computational methodologies applied to discovering and developing PD-1/PD-L1 ICIs for improved cancer immunotherapies with a greater focus in the last five years. The use of computer-aided drug design structure- and ligand-based virtual screening processes, molecular docking, homology modeling and molecular dynamics simulations methodologies essential for successful drug discovery campaigns focusing on antibodies, peptides or small-molecule ICIs are addressed. A list of recent databases and web tools used in the context of cancer and immunotherapy has been compilated and made available, namely regarding a general scope, cancer and immunology. In summary, computational approaches have become valuable tools for discovering and developing ICIs. Despite significant progress, there is still a need for improved ICIs and biomarkers, and recent databases and web tools have been compiled to aid in this pursuit.
The role of sialoglycans in modulating dendritic cell function and tumour immunity
Publication . Silva, Zélia; Soares, Cátia O.; Barbosa, Mariana; Palma, Angelina S.; Marcelo, Filipa; Videira, Paula A.; UCIBIO - Applied Molecular Biosciences Unit; DCV - Departamento de Ciências da Vida; DQ - Departamento de Química; Academic Press
Dendritic cells (DCs) are crucial for initiating immune responses against tumours by presenting antigens to T cells. Glycosylation, particularly sialylation, plays a significant role in regulating cell functions, by modulating protein folding and signalling. This review aimed to provide a comprehensive overview of how sialic acids influence key aspects of DC biology, including maturation, migration, antigen presentation, and T cell interactions. Sialic acids influence DC endocytosis, affecting their ability to uptake and present antigens, while guiding their migration to lymph nodes and inflamed tissues. Removing sialic acids enhances DC-mediated antigen presentation to T cells, potentially boosting immune responses. Additionally, sialylated glycans on DCs modulate immune checkpoints, which can impact tumour immunity. Hypersialylation of tumour mucins further promotes immune evasion by interacting with DCs. Understanding the interplay between sialylation and DC functions offers promising avenues for enhancing cancer immunotherapy.
Beyond sialylation
Publication . Pereira, Beatriz L.; Barbosa, Mariana; Granjo, Pedro; Lochmüller, Hanns; Videira, Paula A.; DCV - Departamento de Ciências da Vida; UCIBIO - Applied Molecular Biosciences Unit; Elsevier Science B.V., Amsterdam.
Defects in sialic acid metabolism disrupt the sialylation of glycoproteins and glycolipids, contributing to a spectrum of diseases, including GNE myopathy (GNEM). This rare disorder is caused by mutations in the GNE gene that encodes for a bifunctional enzyme required for sialic acid biosynthesis, resulting in progressive muscle atrophy and weakness. There is no approved treatment for GNEM, and the number of affected individuals is underestimated. Although hyposialylation is considered the hallmark of GNEM, evidence showed lack of consistent correlation with GNEM severity and unveiled additional roles of GNE that contribute to the onset and/or progression of GNEM. Recent findings indicate that these mechanisms extend beyond glycosylation, encompassing cytoskeletal dynamics, oxidative stress, and muscle regeneration pathways. Understanding how GNE mutations result in a cascade of cellular and molecular dysregulations is crucial for developing targeted therapies aimed at improving the quality of life of patients. This review comprehensively examines GNEM's pathophysiology, clinical presentation, and therapeutic strategies, highlighting key findings on non-canonical GNE functions that account to GNEM clinical outcomes and emerging therapeutic targets. We propose future research directions to explore alternative target pathways that can ultimately support clinical development.
Congenital disorders of glycosylation (CDG)
Publication . Francisco, Rita; Brasil, Sandra; Poejo, Joana; Jaeken, Jaak; Pascoal, Carlota; Videira, Paula A.; dos Reis Ferreira, Vanessa; UCIBIO - Applied Molecular Biosciences Unit; DCV - Departamento de Ciências da Vida; Springer Verlag
Congenital disorders of glycosylation (CDG) are a complex and heterogeneous family of rare metabolic diseases. With a clinical history that dates back over 40 years, it was the recent multi-omics advances that mainly contributed to the fast-paced and encouraging developments in the field. However, much remains to be understood, with targeted therapies' discovery and approval being the most urgent unmet need. In this paper, we present the 2022 state of the art of CDG, including glycosylation pathways, phenotypes, genotypes, inheritance patterns, biomarkers, disease models, and treatments. In light of our current knowledge, it is not always clear whether a specific disease should be classified as a CDG. This can create ambiguity among professionals leading to confusion and misguidance, consequently affecting the patients and their families. This review aims to provide the CDG community with a comprehensive overview of the recent progress made in this field.
An Injectable Thermoreversible Hydrogel Loaded with ManNAc for GNE Myopathy
Publication . Violante, Cristiana; Marques-Da-Silva, Dorinda; Videira, Paula Alexandra; Lagoa, Ricardo; DCV - Departamento de Ciências da Vida; UCIBIO - Applied Molecular Biosciences Unit
GNE myopathy (GNEM) is a rare adult-onset disease characterized by atrophy and weakness of skeletal muscles caused by mutations in the GNE gene. There is no approved therapy, but clinical trials with supplementation with N-acetylmannosamine (ManNAc) alleviated the GNEM-associated decrease in sialylation. Nevertheless, oral intake of ManNAc has shown low absorption and high gastrointestinal adverse effects. In this regard, the aim of this work was to explore an alternative delivery route for ManNAc directly targeting the muscle tissues. For this we investigated the thermal responses of Pluronic F-127 gel and its muscle adhesion after subcutaneous injection, and the kinetics of release of gelencapsulated ManNAc in phosphate buffered saline medium. The results obtained show the thermal response of Pluronic F-127 represents a unique opportunity for its injectability and function as a drug delivery system directly acting on the muscle surrounding area and showing gel stability in the target area. Moreover, the continuous delivery of ManNAc from the gel (20% Pluronic F-127) was detected during 3h, at a continuous rate and slower than using a simple ManNAc solution. In conclusion, the data obtained in this work supports the possible use of the Pluronic F-127 thermoreversible hydrogel loaded with ManNAc in GNE myopathy therapy and research.
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Entidade financiadora
European Commission
Programa de financiamento
H2020
Número da atribuição
825575