INPhINIT Incoming Fellowship – Searching for novel broad spectrum antiviral compounds targeting conformational plasticity and resistance mutations in influenza
fjluque@ub.edu
RESEARCH PRODUCT / RESEARCH GROUP
http://www.ub.edu/cbcg/index.php
Viral infections are one of the major global health threats and their impact can be aggravated by climate changes, increased movement of people, goods and vectors, and the emergence of resistant strains. The development of antiviral drugs against key targets in viral infection is an urgent unmet medical need. For over the past 15 years, our research has explored novel mechanisms of action that enable the identification of compounds able to interfere with the life cycle of the influenza virus. This project aims to identify the molecular events implicated in the activation and biological function of hemagluttinin (HA), which mediates the entry of viruses to the host cell and the fusion of viral and host membranes. Our goal is to explore three strategies focused on distinct molecular processes implicated in the function of HA: i) targeting the structural plasticity through the design of small molecules acting as stabilizers of the inactive form prior to enzymatic cleavage, ii) structure-based optimization of multi-target inhibitors acting at the HA stem, and iii) the development of covalent modifiers able to prevent the release of the fusion peptide. The knowledge gained from these studies will translate into an understanding of the structure-function relationships in HA, particularly regarding the molecular basis of the resistance to current treatments. The results will also exploit novel druggable pockets that may be suitable for the development of novel inhibitors preventing the fusion process. Overall, the outcome of the project will be valuable to develop new chemical entities, leading to an improvement of human health and quality of life.
The project will promote the multidisciplinary scientific and technical formation of the applicant, including the usage of state-of-the-art enhanced sampling techniques, placed at the cutting edge in the biomolecular simulations. In particular, the applicant will be trained in the usage of computational and simulation techniques, including quantum mechanical (QM and QM/MM) calculations for reactivity studies, screening of chemical libraries and ligand binding through molecular similarity and docking techniques, conformational flexibility and structural stability of binding mode examined via Molecular Dynamics simulations, and prediction of binding affinities through free energy calculations in conjunction with structure-based design techniques. Furthermore, the interaction of the applicant with teams involved in organic synthesis, pharmacology and X-ray structure will be encouraged.