The prevalence of drug-resistant infections has challenged the existing treatment regimen using antibiotics. There is a need to discover and employ alternative and complementary therapies to counteract these life threatening infections. In fast few decades, the use of anti-adhesion molecules targeting virulence factors such as lectins has been proven an attractive approach to counteract the infections by disarming the pathogens. This has been achieved by the development of glycomimetic inhibitors of various lectin targets. Within the scope of the PhD4GlycoDrug consortium, this thesis work aimed to design glycomimetic antagonists of the N-terminal domain of the BC2L-C lectin (BC2L-C-nt) from the drug-resistant pathogen Burkholderia cenocepacia. To achieve the objectives, this project employed a fragment-based approach to design glycomimetic antagonists of the target protein (BC2L-C-nt). This approach under the structure-based drug design involved the application of the computational and experimental methods to achieve the objectives of the research. The initial studies were focused towards the binding site prediction and target evaluation by computational tools which identified additional druggable regions near the fucoside binding site in the lectin (BC2L-C-nt). These additional regions have been explored further to evaluate the druggability by employing virtual screening of a small fragment library in the vicinity of the fucose-binding site. This identified an interesting region (region ‘X’) that could host the drug-like fragment by establishing some key interactions in the site. The interactions of the fragments with the lectin have been confirmed using a group of biophysical techniques, including X-ray crystallography.
Anna Bernardi (University of Milan), Laura Raimondi (UNIFI), Anne Imberty (CERMAV), Annabelle Varrot (CERMAV)