Resistance to antibiotics is a response of pathogen microorganisms to the use of these drugs. Unfortunately, abuse implies their loss of efficacy. Bacteria stop being sensitive to their effects, being necessary novel generations of antibiotics to combat infections, with the concomitant more toxic to health.
The advantages in using peptides as drugs are their high specificity coupled to a large biological activity. They present a great diversity as therapeutic targets (antibiotics/antifungals, antivirals, cancer, etc). However, several difficulties have prevented them from being widely used as drugs. Peptides show low metabolic stability, they are rapidly degraded in vivo by proteases and the most common form of administration is intravenously, which highly prevent its degradation. In principle, these problems should be minimized with lasso-peptides. The rigidity and high packing (lasso-type) endow them with enormous stability against proteolytic degradation, physical/chemical denaturants. The first years of the project, at TSRI and under the guidance of Prof. Baran, we focused on exploring different synthetic methodologies with the final aim of preparing lasso peptides to study their recognition features and eventually their applications as putative drugs.
In the last year of the project, carried out at the Center for Cooperative Research in Biosciences (CIC bioGUNE) under the guidance of Professor Jimenez-Barbero, we focused on the study of protein-ligand molecular recognition processes of biomedical interest. In particular, I was trained in the applications of state-of-the-art Nuclear Magnetic Resonance (NMR) techniques and computational methods in this area.
Since the target Microcin J25 lasso peptide was elusive and could not be prepared either by organic or enzymatic synthesis, maintaining the essence of the DoA work-packages, we focused on the molecular recognition study of a biologically highly relevant system: the Heparan Sulfate/FGFR Ig2 system, of interest in cancer and inflammation.
