Our Research

The research activities of the Institute focus on scientific areas and topics with direct or indirect social implications. 

The Institute continues to build upon its experience in the synthesis and mechanism of action of biologically active substances. Most of the research is carried out in the laboratories of the Institute and with collaborating academic groups worldwide. The staff are assisted by fellows who are supported by public and private research grants. To extend the scope of its research, the Institute encourages collaborative work and the exchange of research workers with Italian and international laboratories and universities. Research reports are generally published in high quality international journals of chemistry, medicinal chemistry and biochemistry.

The Institute’s activities concentrate on experimental research, but also include educational activities and the organization of scientific meetings.

Heparin and heparan sulfate are linear, sulfated, polydisperse polysaccharide of animal origin belonging to the class of glycosaminoglycans (GAGs). Heparin and low-molecular weight heparins (LMWHs) are widely used in anticoagulant and antithrombotic therapy. LMWHs and non-anticoagulant heparin derivatives are also promising candidate drugs against cancer and inflammation. The structure of heparin and other GAGs is complex and unravelling features associated with their diverse biological activities, with the eventual aim of dissecting them and generating more potent and more specific drugs, requires convergent application of chemical and enzymatic cleavage as well as advanced NMR and LC-MS methods. The systematic chemical and/or enzymatic modification of heparin and related GAGs is a valuable strategy for structure-activity studies as well as for obtaining novel molecules endowed with better binding properties towards proteins associated with diverse biological activities.

Research topics include:

  • Analytical profiling and chemo-physical properties.
  • Structure and molecular conformation.
  • Anticoagulant and antithrombotic heparin species
  • Non-anticoagulant heparins as potential anticancer agents
  • Non-anticoagulant heparins as potential anti-inflammatories
  • Non-anticoagulant heparins as inhibitor of hepcidin.

selected publications

Chemometric techniques, particularly multivariate analysis methodologies (PCA), have long been used in the analysis of complex datasets, for example, in the metabolic profiles obtained through chromatographic and / or spectroscopic methods. The application of these approaches to one-and two-dimensional NMR spectra can be used to detect unknown contaminants as well as to differentiate the heparin and heparin-derivatives on the basis of their structural features and animal/organ of origin. The Ronzoni Institute has amassed libraries of spectra of validated “bona fide” heparin and heparin-derivatives samples defining the current statistical definition of each class of product.

Research topics include:

  • Chemometric analysis of heparin and crude heparin NMR spectra

selected publications

 



Protein-carbohydrate interactions are the key events of many important healthy and pathophysiological processes.  A deeper understanding of these interactions at the molecular level is critical for the development of new therapeutics. Our research interests focus on the characterization of the 3D structure of carbohydrates and their molecular recognition by proteins and bio-macromolecules using complementary structural biology techniques, such as solution NMR, solid state NMR, molecular dynamics simulation, zeta-potential and dynamic Light scattering.

Research Topics include:

  • Growth factors and antithrombin binding oligosaccharides
  • Interaction of heparin/low molecular weight heparin with platelet factor 4
  • Interaction of influenza A viral hemagglutinins with sialylated Glycans
  • SARS-CoV2/sulfated polysaccharide interaction

selected publications

The number of complex drug substances, including biologics, present in various pharmacopoeias has increased during recent decades. These drugs are distinct from chemically synthetized pharmaceutical products, since they do not represent a single entity, rather, they are a complex combination of substances or heterogeneous mixtures. They are usually extracted from natural sources, prepared chemically, or produced by biotechnological methods. Our research is aimed at the development of orthogonal analytical approaches to assess the structural features of these drugs, particularly LC-MS and NMR techniques.

Research topics include:

  • Low molecular weight heparin
  • Glycosaminoglycan mixtures
  • Glatiramer acetate
  • Pentosan polysulfate
  • Conjugate extrogens
  • Monoclonal antibody
  • Defibrotide

selected publications

The institute has made numerous original contributions to the chemistry of carbohydrate polymers, with an emphasis on chemical regioselective modification of polysaccharides as a strategy for deriving relationships between structure and properties.
The Institute has expertise in high molecular weight polysaccharides, such as hyaluronic acid, chitosan, alginate, gellan gum, cellulose etc., typically used in the pharmaceutical or food technology fields. In particular, the group’s activity is focused on the functionalization and characterization of products by several chemical-physical techniques, including solution and solid state NMR, rheology and light scattering techniques. One example is the study of high viscosity/gel solutions containing hyaluronic acid, which presents a significant challenge for the prediction of the biological activity of the product under physiological conditions. This research informs the design and formulation of the polymer in cosmetics, food and biomedical applications.

selected publications

The group has established experience in peptide synthesis, with emphasis on peptidomimetics of biological interest and the study of their structure-activity relationship and has made significant contributions to the synthesis of novel pseudo-amino acids and to the development of original methods for the incorporation into peptides of extremely hindered building blocks.  
In recent years, the group’s activity has focused on the synthesis of bioactive heparin/heparan sulphate oligosaccharides.  The synthetic targets are currently aimed at synthesizing potential heparanase inhibitors. The research activities are conducted under the supervision of Dr M. Petitou, “father” of the synthetic heparin pentasaccharide, fondaparinux.  

selected publications

 

A number of polysaccharides from natural sources, such as cellulose, chitin, chitosan and starch, are extensively studied and have well-established industrial applications. Among these, the starch-derived cyclodextrins are endowed with the unique property of forming inclusion complexes with a number of organic molecules whose size and shape fit into their macrocycles; such inclusions can be exploited for protecting the guest molecules and modifying their intrinsic solubility and properties. Advances in morphological and structural analysis of oligo- and polysaccharides and their derivatives provide deeper insights into those structural features that determine their optimal application in various fields and to generate new products.

Research topics include:

  • cellulose derivatives
  • cyclodextrin
  • synthetic polymers
  • polyhydroxyalkanoate

selected publications

The Institute contributed to the first applications of nuclear magnetic resonance (NMR) spectroscopy to carbohydrates and their polymers and is currently engaged on several fronts with various international organizations to verify the equivalence of generic / biosimilar drugs through the development of new, proprietary analytical methodologies and their application to quality control.
In 2007-2008, working with MIT and the Food and Drug Administration (FDA) in the USA, the Institute made a key contribution to the solution of the “heparin crisis” that had caused over one hundred deaths in the United States and worldwide by identifying the contaminant responsible.

selected publications

CP-MAS (Cross Polarization Magic Angle Spinning) NMR spectroscopy is an important means of studying materials in general. Solid state NMR spectroscopy is a non-destructive technique and is independent of the solubility of the samples under examination. It lends itself to the characterization of polysaccharides, such as cellulose, starch and chitin. Through measurement of the relaxation and polarization transfer times (T1 rho and TCH), morphological properties and the homogeneity of the systems can be investigated, including the interaction between organic and inorganic components.

Research topics include:

  • Cellulose and derivatives
  • Starch
  • Chitin and chitosan
  • Synthetic polymers

selected publications

Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni – Fondazione non profit – Via G. Colombo 81 – 20133 MILANO – igr-ronzoni@legalmail.it – C.F. 01110900154