• Medicinal Chemistry 3 3410 749x388 © 2016 IIT 5153
  • NMR Laboratory 2 3412 749x388 © 2016 IIT 5155
  • In Vivo Pharmacology 3408 749x388 © 2016 IIT 5151
  • Medicinal Chemistry 2 3409 749x388 © 2016 IIT 5152
  • NMR Laboratory 1 3411 749x388 © 2016 IIT 5154

The D3 PharmaChemistry Line possesses competences and technologies to start and advance drug discovery projects and to provide support to the progression of projects in the area of drug delivery and diagnostics. 

Activities

The medicinal chemistry group develops chemical series of interest for drug discovery projects. The starting points for medicinal chemistry programs are the ‘hits’ identified by fragment-based approach or screening of the IIT compound collection of more than 15,000 compounds. The biological activity of hits is progressively improved by the synthesis of analogues in order to discover ‘lead’ compounds. Drug-like properties of the leads are then optimized through an iterative process with the ultimate goal of identifying candidates for preclinical development and eventual clinical testing.

The laboratory is a state-of-the-art infrastructure dedicated to the development of analytical and bioanalytical methods for the study of small molecules and biomolecules. Several assays, including solubility and metabolic stability tests, are available to characterize new compounds originating from drug discovery projects. Moreover, the pharmacokinetics profile is determined for the most interesting molecules. An extensive expertise exists on proteomics, metabolomics and lipidomics. These technologies are applied to study the interaction of compounds and new materials/nanomaterials with living systems in order to identify biomarkers of activity and/or toxicity.

The activities of the NMR lab span from the structural and purity determination of organic compounds to the study of protein-protein and small molecule-protein interactions. NMR-based binding and functional assays are developed to discover modulators of protein activity as starting points for drug discovery projects. Activities also include metabolomics studies aimed at the identification of biomarkers for assessing the activity and/or toxicity of potential new drugs either in vitro or in vivo.

The laboratory is in charge of assessing the ability of small molecules to modulate the activity of pharmacologically relevant targets such as enzymes and receptors. Cell-free and cell-based assays are developed and used to study the activity and the mechanism of action of the compounds of interest. These studies extend to the evaluation of the safety profile of small molecules and new materials/nanomaterials, and to the development of models to possibly predict the biological activities of selected drug delivery systems and nanomaterials.

The in vivo characterization of compounds and nanomaterial-based drug delivery systems for their efficacy and potential toxicity is key to advancing drug discovery and drug delivery projects. The group performs studies to assess pharmacokinetics, efficacy in animal models of disease, and preliminary acute toxicity of drugs and drug delivery systems. These studies are complemented by the investigation of changes in the levels of endogenous biomolecules to possibly shed light on the mechanism of action and/or toxicity of the tested materials.

The group is focused on nanotoxicology assessments, which link the physicochemical properties and functionality of manufactured nanomaterials with specific hazard outcomes. These efforts include: the development and testing of Safety by Design measures to facilitate the identification of novel and safer nanomaterials; standardization of analytical methods in the nanoregulatory framework to characterize nanoparticles’ (NP) physical-chemical properties (NP reactivity by abiotic systems, NP surface charge and size, NP agglomeration and dissolution) and their biotransformation processes in bio-fluids related to human exposure (e.g., gastrointestinal, lung, sweat, etc.); 3D cellular cultures (gastrointestinal or lung epithelia) and their interactions with bio-transformed NPs/drugs, grouping approaches based on NP mode of actions, in vitro/in vivo correlation. The results of these studies are then used to provide advice for the development of regulatory measures and to develop analytical tools, which will increase the level of safety related to the manufacture and use of nanomaterials. These tools are then tested for their applicability in nanomedicine using a range of nanoparticles of interest for biomedical applications. A research line is focused on the development of protein-based nanocarriers for oral delivery of antioxidant molecules with improved stability in the gastrointestinal tract and bioavailability.

Laboratories

The Line is comprised of various laboratories and groups with a broad range of competences including Synthetic and Medicinal Chemistry, Analytical and Bioanalytical Chemistry, NMR Spectroscopy, in vitro and in vivo Pharmacology, Nanotoxicology, and Lab Automation and Data Management. Thanks to those competences and state-of-the-art instruments, the D3 PharmaChemistry can undertake various tasks such as synthesis and characterization of potential new drugs, development in vitro assays to evaluate the biological activity and/or toxicity of compounds and materials, assessment of the efficacy of drugs and drug delivery systems in animal models of disease, quantification of drugs in biological fluids and tissues, and search for potential biomarkers of activity and/or toxicity of small molecules and new materials. Leveraging on existing competences, the Line applies a multidisciplinary approach to support specific research needs of IIT groups in the area of life sciences and intelligent drug delivery systems.

Collaborations

  • Graphene Labs (V. Pellegrini, F. Benfenati):  Metabolomics of neurons exposed to graphene
  • Smart Materials (A. Athanassiou):  In vitro/in vivo characterization of new materials for biomedical applications
  • Nanobiointeractions and Nanodiagnostics (P.P. Pompa): In vivo characterization of nanomaterials for the
  • Nano Carbon Materials (S. Giordani):  In vitro characterization of carbon nanomaterials
  • Istituto Giannina Gaslini (N. Pedemonte - L. Galietta):  Task Force for Cystic Fibrosis project - Discovery of new drugs for the treatment of cystic fibrosis
  • Istituto Giannina Gaslini (R. Ravazzolo):  New treatment strategies for Fibrodysplasia Ossificans Progressiva
  • Telethon Institute of Genetics and Medicine (TIGEM – L. Galietta): New therapeutic targets in cystic fibrosis lung disease
  • University of Genoa (DIMES, R. Cancedda):  Proteomics studies on exosomes