An inhibited uPA

‘Key’ that inhibits molecules involved in cancer spread uncovered

Some of the enzymes in our body can have both positive and negative effects. This is the case for the urokinase human enzyme (uPA), which has the positive effect of dissolving blood clots, but also stimulates cancer cell motility and has been identified as a major player in various stages of cancer, particularly in cancer metastasis, and in inflammatory diseases, such as rheumatoid arthritis. 

In order to avoid this negative effect, uPA must be inhibited. A new patent developed at Ca’ Foscari University of Venice uses bicyclic peptides to selectively detect the uPA and inhibit its activity, with higher effectiveness than inhibitors currently on the market. This new type of miniaturised antibodies has been created by a research team led by Alessandro Angelini, professor Biochemistry at Ca’ Foscari’s Department of Molecular Sciences and Nanosystems.

Scientific research had already been conducted in this field, generating chemical molecules that were able to block uPA. However, the inhibitors previously developed have limited effectiveness and cause side effects, because they are not selective: in addition to targeting uPA, they can also inhibit other molecules that are not cancerous.

Bicyclic peptides are made by two chains of amino acids and create bonds with the uPA molecule that needs to be blocked. The risk of missing the target is therefore greatly reduced, resulting in a reduction of side effects. 

The research involved an initial computational phase during which advanced artificial intelligence methodologies were employed in order to find the best ‘fit’ between the amino acids and the various parts of the uPAs, in terms of type and positioning. Thousands of configurations were created before the most effective ones were found.

The second phase of the research involved experimentation, i.e. the chemical synthesis of molecules and the ensuing establishment of their three-dimensional structure. Peptides were crystallised in order to obtain their molecular structure using x-ray diffraction techniques and to test their selective interaction with the uPA target molecule.

As a result, a series of bicyclic peptides was developed. These peptides are characterised by high potency, selectivity, stability, and good tissue penetration. They are also less toxic than the ones currently on the market because they specifically target uPAs. 

This creation was patented (more information on patents is available here) in order for it to be employed in pharmaceutical products. Thanks to the combination of bicyclic peptides, transporters, and other useful substances, patients will be offered a new tool to limit the spread not only of cancer, but also of other inflammatory diseases, such as rheumatoid arthritis. This research is currently available for further collaborations, development and marketing.

Author: Enrico Costa / Translator: Joangela Ceccon