This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant agreement Nº 847635.
Department of Organic Chemistry
Facultad de Ciencias Químicas
The Medicinal Chemistry Laboratory is made up of 15+ members. At this moment we are one full professor, four associate professors, two postdoctoral researchers, five graduate students, and three master students. The staff includes researchers with different areas of expertise (organic chemistry, medicinal chemistry, biochemistry, cell and structural biology, and computational modelling). The main research interest of our group is to address challenging diseases using multifaceted drug discovery approaches. The last years have witnessed the relentless progress of different scientific and technological advances in the drug discovery field that are opening up a wealth of unexplored possibilities for developing novel pharmacological strategies to face challenging diseases. In addition to the highly valuable target-based approach, which has contributed to the development of countless new drugs in the last years and remain fully up to date, two strategies are revolutionizing the pharmacological landscape for many hard-to-treat diseases. These are phenotype-based and immunotherapy drug discovery. Hence, in our laboratory we use these three different approaches aimed at i) the validation of new targets for spinal cord injury (LPA receptors) and progeria (ICMT and progerin); ii) the identification of new targets involved in important disorders such as leukemia and senescence; and iii) the development of new antibody-drug conjugates for the treatment of tuberculosis.
We count with a laboratory fully equipped with all the usual instrumentation of modern organic chemistry and chemical biology laboratories to successfully carry out the experiments detailed in this proposal. Additionally, we have access to excellent core facilities for research, including extensive NMR (300–700 MHz range) and MS services (FTMS-Apex Q IV, MALDI-TOF/TOF, LCMS-8030 Triple Quadrupole). X-ray crystallography, elemental analysis, animal services, genomic, microscopy, and flow cytometry services are also available. In summary, we have all the resources needed for a successful completion of the project.
Tuberculosis (TB) is the leading infectious cause of death worldwide. The current treatment for TB involves a multidrug regime with up to 4 drugs (isoniazid, ethambutol, rifampicin, pyrazinamide) for six months in uncomplicated pulmonary TB, and up to 24 months of therapy for multidrug resistant-TB strains, which led to a high risk of lack of compliance to the medication. The low efficacy of the current treatments is mainly due to their poor capacity to reach the granuloma, an inflammatory mononuclear cell infiltrated that provides a survival niche from which the bacteria may disseminate. Hence, targeted drug delivery could help improving clinical success of anti-TB agents by selectively directing the drug to the granuloma to eliminate these bacterial niches.
In this regard, site-specific antibody-drug conjugates (ADCs) could constitute a novel approach for treating TB. This strategy involves the attachment of a monoclonal antibody, directed to M. tuberculosis or to antigens in the surface of the macrophages of mammalian cells, to an anti-TB drug that is selectively released inside the infected cell through a cleavable linker. For therapeutic applications, the ADC must satisfy demanding criteria concerning speci?city, safety, and stability to achieve effective delivery of the drug to the target.
The aim of this project involves the following steps: (i) optimization of ADCs previously developed in our laboratory; (ii) screening of their antibacterial activity against M. tuberculosis; (iii) study of the localization of the synthesized ADCs and assessment of their ADME(T) properties; and (iv) biological evaluation as anti-TB drugs (in collaboration with Prof. Rafael Prados, UAM, Madrid).