NCBR seminar: Marko Anderluh

Marko Anderluh is a professor of pharmaceutical chemistry at the Faculty of Pharmacy, University of Ljubljana, where he serves as a university lecturer and researcher. His scientific work focuses on the design and synthesis of bioactive molecules, their biological testing, and the optimization of their properties for potential drug development.

Abstract:

In the first part of the talk, I will focus on our quest in design of DNA gyrase inhibitors. We have focused on Novel bacterial type II topoisomerase inhibitors (NBTIs) that stabilize single-strand DNA cleavage breaks by DNA gyrase. Although the class is known for almost two decades, their exact mechanism of action has remained hypothetical until now. To address this issue, we have designed a small library of NBTIs with an improved DNA gyrase-binding moiety resulting in low nanomolar inhibition and very potent antibacterial activity. They stabilize single-stranded cleavage complexes and, importantly, we have obtained the crystal structure where an NBTI binds gyrase–DNA in a single conformation lacking apparent static disorder. This directly proves the previously postulated NBTI mechanism of action and shows that they stabilize single-strand cleavage through asymmetric intercalation with a shift of the scissile phosphate. The crystal structure shows that the chlorine forms a halogen bond with the backbone carbonyls of the two symmetry-related Ala68 residues. To the best of our knowledge, such a so-called symmetrical bifurcated halogen bond has not been identified in a biological system until now. From this more chemico-biological part of the research, we have moved to more medicinal chemistry-related work in which we optimized the NBTI potency and diminished hERG inhibition. At last, we performed in vivo studies (mouse thigh infection model), which show efficacy of our compounds in in vivo setting. In the second part of the talk, I will present our results in designing potent and selective galectin-8 inhibitors. We have made a series of 3-substituted D-galactal derivatives, 3-lactoylgalactosides and 3-triazolyl-1-thiogalactosides as galectin-8 inhibitors and show the influence of various substitutions on D-galactose and D-galactal core on the galectin-8 affinity and selectivity. The synthetic data will be corroborated by structural data that allowed us drug design fine-tuning. Finally, I will present a new optimized focused D-galactosides library that reached nanomolar Kd on galectin-8 for the first time. In particular, I will present recently published data on how we obtained such affinity by new D-galactosides that form non-canonical cation-p interactions with Gal-8N. will also present some data on how galectin-8 may be used in Pseudomonas aeruginosa keratitis and other diseases.