1. Strategies to control microbial infection
iMed.ULisboa scientists are committed to spin innovative research on pathogen evolution to other forms of virulence and drug resistance, and develop molecular strategies to control microbial infection. Part of our bacteriophage research and antibody discovery has been developed in collaboration with biotechs (TreatU, TechnoPhage). Moreover, we collaborate with institutions worldwide in molecular epidemiology and genome-wide analysis of multi- and extensively drug-resistant M. tuberculosis. We have identified genetic determinants of drug resistance, including new mutations and interactions between drug resistance-associated genes, which highlight the role of efflux pumps and provide hints to rapid molecular diagnosis. We are also often involved in assessment of trends in health, providing global and national estimates on infection to improve control measures and inform patient management. Finally, iMed.ULisboa scientists have developed a novel and potent fusion inhibitor of HIV infection based on a rational strategy for synthetic antibody library construction. Engineered transcriptional modulators based on customizable transcription activator-like effector (TALE) proteins can induce gene expression from the HIV-1 long terminal repeat promoter, and combinations of TALE transcription factors can synergistically reactivate latent viral expression in cell line models of HIV-1 latency.
2. Diagnostic and therapeutic tools in non-communicable diseases
A lack of tractable non-invasive biomarkers has impeded diagnosis and hampered drug development and the conduct of clinical trials in many non-communicable disorders. We have recently profiled miRNAs in mice and humans with non-alcoholic fatty liver disease progressing to steatohepatitis (NASH) and hepatocellular carcinoma, and identified several changes with diagnostic potential. We have also shown that multitargeting strategies involving genetic (e.g. miRNA) and pharmacological regulation of cell metabolism and cell fate strongly impair NASH development. Further, microbial energy metabolism and the gut-liver axis should be regarded as prospective therapeutic targets. Our work in the field has been recognized by the scientific community and by EU H2020 IMI2 initiatives, funding the LITMUS consortium with the overarching aim to develop, robustly validate and advance towards regulatory qualification biomarkers that diagnose and risk stratify NASH progression and fibrosis. iMed.ULisboa scientists will specifically work on developing consensus on preclinical models and then back-translate biomarkers for validation in these models. EU Marie Curie funding for innovative training networks (FOIE GRAS consortium) and EU Joint Programme funding for neurodegenerative diseases research (MADGIC consortium) additionally distinguished our work. Of note, we have further developed bile acids as a group of promising liver produced modulators of cell death/survival, protected by patents and licensed by spin-off pharmaceuticals, which entered phase I/II clinical trials to treat amyotrophic lateral sclerosis.
3. Chemical biology and multivalent platforms
The chemical functionalization of proteins is an invaluable tool to prepare therapeutically useful conjugates and is a major area of investment for pharmaceutical companies. iMed.ULisboa scientists focus on discovering innovative stimulus responsive bioconjugation methods to construct “smart” targeting drug conjugates. Recently, we found that carbonyl benzene boronic acids generate iminoboronates that allow the reversible functionalization of lysine and N-terminal cysteine residues. Our findings generated a surge of interest among the chemical biology community, and the iminoboronate technology is now a widely used strategy to reversibly functionalize biomolecules, recognized through prizes and honours. In addition, the expedient access to molecular complexity is important not only to explore the chemical space of new leads but also to create functional multivalent constructs that may be used to interfere with biological systems. In this field, we discovered that boron offers a unique bonding profile that can be used to generate well-defined reversible multivalent constructs. This innovative strategy enabled the synthesis of natural product like motifs, potent inhibitors of human enzymes, modular fluorescent dyes and multivalent reversible cancer cell targeting drug conjugates. The Portuguese pharmaceutical company Hovione recently acquired the patent rights of boronated multivalent technology.
4. Multitargeting tools for malaria drug discovery
Elimination of malaria has been set as WHO Sustainable Development Goal for 2030. This effort requires novel agents active against all stages of the parasite complex life cycle, and preferably acting on underexploited targets. iMed.ULisboa scientists focus on identifying compounds with multistage antimalarial activity, and were one of the first to provide preclinical proof-of-concept that hybrid drugs with a multitarget profile can block the development of all forms of malaria parasites. Scientists and scientific associations have recognized the contribution of the hybrid- multi-stage concept to malaria elimination. Importantly, the hybrid approach has evolved to highly potent modular small molecules, and one chemotype that fulfils the target candidate profile criteria for targeting asexual parasites and hepatic schizonts and is now under evaluation by the Medicines for Malaria Venture.
5. Nanovaccines to trigger immune antitumour responses
A stepwise approach has elucidated the effect of nanovaccine composition and developed a method of antigen association that trigger anticancer immune responses. Work was developed from nanocarrier uptake by antigen presenting cells, expression of activation markers at dendritic cell surface, T cell activation and expansion, up to inactivation of T cell memory, key to protect patients against recurrence. Final proof-of-concept was provided regarding the immune therapeutic effect of our novel nanoparticle system using melanoma and Her2-specific breast carcinoma models. These studies highlight the potential of nanovaccines to trigger broad immune responses against breast carcinoma resembling human disease, particularly the low expression of cancer-associated antigens. Our approach provides further understanding of nanocarrier mechanisms of action and cellular dynamics of outmost importance to guide the design of optimized cancer vaccines.
Other recent highlights:
1. Collaboration and leadership development
The translation of discoveries to the clinics is speeding with efforts to find more precise ways of managing disease. iMed.ULisboa leads a large recently funded project, involving academia, biotech and pharma industry, hospitals, patients and medical associations, supported by European structural funds. POINT4PAC will develop a platform for discovery and early development of innovative technologies, therapies, and solutions for treatment, prevention and control of cancer. We combine complementary state-of-the art resources in phenotypic HTS and medicinal chemistry, with antibody-drug conjugate technology and nanoparticle-engineered formulation for delivery to the right target in the right cell. By involving a large team of researchers at iMed.ULisboa, including young PIs and newly recruited postdoc scientists, this project is exemplar for future inclusive multidisciplinarity and leadership.
2. Scientific platform development and partnering
iMed.ULisboa has recently created the Molecular BioScreening Platform that supports scientists seeking to understand how molecular processes govern biological function. We apply a collaborative working model to identify and develop novel chemical compounds, which elicit specific biological responses. We recently screened > 250,000 pharma molecules using phenotypic HTS to discover modulators of cell function with the potential to become new drugs. The hits are now feeding hit-to-lead medicinal chemistry projects at iMed.ULisboa. We specifically invest in assay development using improved 3D culture- and stem cell-based approaches funded by H2020 or pharma (AstraZeneca, ECBio, Intercept). These high-level platforms will set a paradigm at iMed.ULisboa for academia-industry partnerships and inclusion in international research infrastructures (EU-OPENSCREEN; ADDC).
International cooperation accelerates therapies and improves diagnosis. iMed.ULisboa integrates a pioneering European consortium that aims at new diagnostic tests for liver disease. Funded by the H2020 IMI2, LITMUS brings together clinicians and scientists from prominent academic centres across Europe with companies from EFPIA. We collaborate also in molecular epidemiology and genome wide association studies to identify determinants of microbial drug resistance. This strategic international research portfolio encompasses studies of biology and health-related policies and includes assessment of risk and protective factors; screening and identification of at-risk individuals; development of risk-reduction strategies; and translation, implementation, and dissemination of preventive interventions. We often publish with international co-authors (ca. 70% papers), and organize or chair high profile international conferences.
4. Recruitment of outstanding workforce
Propelled by recent successful research initiatives, iMed.ULisboa and FF/ULisboa have built a strong political will on renovating teaching and research staff. Following the admission of twelve highly qualified investigators in 2007-08, eight new investigators were recruited in 2012-15 in competitive calls funded by FCT. More recently, FFULisboa set the stage for future recruitment initiatives and signed seven new contracts of assistant professor level in 2016-17.
5. Research training
iMed.ULisboa has also progressed tremendously in scientific training programmes dedicated to PhD and Postdoc levels, and to young undergraduate and Master students. We lead the PhD Programme in Medicines and Pharmaceutical Innovation financed by FCT since 2015. We also promote four other FCT funded training initiatives, all multi-institutional, including the PhD Programme in Medicinal Chemistry. Further to the above, two H2020 Marie Curie European Training Networks have recently expanded our ability to facilitate the development of inter- and cross-disciplinary research teams and to stimulate translational research training.