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28 ottobre 2020
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Synthesis Group

Since 1990 the research interest of Ronzoni focused also on Peptide Chemistry, with particular attention on peptidomimetics.

The discovery of the physiological role of a great number of peptides stimulated researchers  all over the world towards design and synthesis of peptidomimetics ( or peptide-like molecules).   Since natural peptides seldom can be used therapeutically as drugs, because of the problems associated with low absorption, rapid metabolism and low oral bioavailability, many efforts aimed to modify the natural sequence of the amino acids of bioactive peptides achieved a desired, very focused effect.

Synthetic non-natural peptides (or pseudopeptides or peptidomimetics) have the advantage of providing new functionalities that can circumvent natural processes in the body.   For example, they become able to perform functions that are not available with the natural materials, such as binding to and penetrating cell membranes and resisting degradation by enzymes.

In our laboratories, we researched about modified natural peptides, following different chemical approaches and aiming to different pharmacological activities:

Peptides active in wound healing and tissue repair

Glycyl-histidyl-lysine (GHK) is a growth factor isolated from human plasma, having an important role in several physiological processes, such as chemoattraction of cells, angiogenesis, neurogenesis, associated with wound healing and tissue repair.   The mechanism of its activity was attributed to its function as a transporter of ionic copper (II).

Despite this interesting activity, the instability of GHK in plasma may preclude the maintenance of significant tissue concentration when administered either topically or intradermically.

This stimulated us to design GHK analogues having potentially the same spectrum of biological activity together with enhanced stability to enzimatic degradation.

Partially retro-inverso analogues of GHK were synthesized in which the CO-NH bond between histidine and lysine was modified as NH-CO;  this modification is not expected to perturb the spatial distribution of the side chains.   The plasmatic stability of the new pseudopeptides resulted enhanced up to two order of magnitude  and interesting activity was shown for some products of the series obtained.

Pseudopeptides with antithrombotic and antiangiogenic activity   (RGD analogues)

Recently, extensive efforts have been directed towards the discovery and synthesis of RGD mimetics.   A great number of physiological processes are regulated by extracellular adhesion proteins (fibrinogen, fibronectin, vitronectin, von Willbrandt factor...), which, interacting with specific receptors found on the cells walls, regulate migration of the cells and their proliferation.

These receptors are known as integrins, among which the most studied are:

  • 1)      a IIbb3, expressed by plasma platelets and involved mainly in the platelet aggregation.
  • 2)      a vb3, expressed by almost all cells, that binds to a number of different ligands, beeing vitronectin the most represented, and involved in many cell-adhesion processes such as angiogenesis, tumor metastasis, bone remodelling.

The binding of different extracellular matrix proteins to their receptors is mediated by the sequence RGD (Arginine-Glycine-Aspartic acid) and, therefore, antagonists of this natural sequence constitute an attractive goal for development of many different therapeutic agents.   Modulating the spatial shape (conformation) of small peptides containing the active sequence, it is possible to obtain specific antagonists of  a IIbb3 integrin (enhancing antithrombotic activity) or of a vb3 integrin (oriented towards antiangiogenic and antitumoral activity).

We choosed to search for a constrained ideal conformation with the introduction  of  a-difluoro- or trifluoroamino acids into key positions of a peptide containing the RGD sequence.   This type of  substitution is known to influence the three dimensional conformation of a peptide, reducing the spatial flexibility of the backbone and the side chains.

Through this original approach, which urged us to study new synthetic pathways, we could obtain a number of linear and cyclic RGD mimetics containing a-difluoro- and a-trifluoroamino acids, which are now under biological screening.

In parallel, a research is beeing carried out in order to look for suitable carriers that help in the administration and transport of  peptides in vivo.

See publications 22-32.

Dr. Annamaria Naggi