The aim of the BMWZ group of Structural Chemistry is to characterize the structure and the mode of action of RNP complexes involved in RNA processing, in the regulation of gene expression and in host-pathogen interactions. This knowledge allows the design of small molecules inhibitors or enhancers of the activity of the RNP machinery and consequently human intervention in disease processes.
The regulation of cellular processes and host-pathogen interactions through RNP complexes offers the opportunity to identify new drug targets. This is highly relevant in an era when human health is challenged by the outbreak of new infectious diseases, which spread rapidly because of worldwide mobility. Pathogens with increasing resistance to established treatment represent another threat to human health. Antimicrobial resistance imposes higher costs on the health system, increases the number of disabled individuals and threatens to turn curable diseases into incurable ones. Finally, the increasing age of the population intensifies the demand for treatment of age-related pathologies, such as cancer and neurological degeneracy. In this picture the emergence of new drug targets, together with a molecular understanding of their function, represents an important perspective.
So far, most of the structures of high-molecular-weight RNP complexes have been obtained by X-ray crystallography. Yet, much less RNP structures are available to date as compared to protein complexes. In this context the question arises whether X-ray crystallography is always the best structural method to study RNPs. Among the advantages of crystallography is the high resolution, which can be achieved independently of the molecular size. However, crystallography requires the molecule to be in a unique well-defined conformation that allows packing in an ordered lattice. Flexible molecular machines are not easily found in this state, resulting either in failures to crystallize or in structures that are incompetent for activity.
As an alternative to X-ray crystallography, our team develops an interdisciplinary approach that leverages on solution-state methodologies to access the structure, the dynamics and the conformational changes of high-molecular-weight RNP complexes during their activity cycle.
In addition, we develop methodologies to support structure-based drug design (SBDD). The search of new active molecules starts with screening experiments for the identification of possible interaction partners and proceeds to the development of the small molecule leads into efficient drugs, with both high affinity and specificity to the target and good pharmacokinetic properties. At this stage, structural information on the active ligands in complex with the receptor is essential. We are the developers of INPHARMA (Interligand NOEs for PHArmacophore Mapping), a NMR-based methodology designed to access the relative binding mode of pairs of competitive ligands without need of large protein amounts, recombinant material or expensive labeling schemes (see section Drug Design).
Detailed Research Subjects
More detailed information on the following research subjects is here available: