Rational design, synthesis and characterization of molecules of therapeutic interest and their transport through nanovectors.
Reposition of existing drugs through computational simulations; evaluations of efficacy and toxicity
Dr Camillo Rosano
Background
The preparation of modern drugs is based on three cornerstones: a) pharmacogenomics, which seeks specific significant targets at the base of the diseases towards which to direct drugs capable of exclusively targeting these pathological targets; b) pharmacogenetics c) drug delivery, that is the discipline concerning the transport and / or release of active molecules at the desired concentrations, in the time required for their effect and in the site where they must act. Over the last decade, this working group has distinguished itself in this research area as demonstrated by the numerous scientific publications written and published in international journals. Three lines of research have been particularly followed: the study of Calix[n]pyrrole derivatives for their possible use as drugs, the study of these same macrocycles as new vectors for drug delivery, molecular docking protein: small molecules in collaboration with various Italian and foreign Bodies and Universities. In this context, the studies on Calixpyrroles were particularly interesting. These compounds have in fact proved to be of great interest for a possible use in therapy also following the in vitro validations and the in vitro and ex-vivo toxicity tests that we carried out in our laboratories. Furthermore, by means of differential proteomics, mass spectrometry and bioinformatics analyzes, we were able to identify some molecular mechanisms that these compounds seem to be able to modulate in some tumor cell lines. Tests on cell proliferation, induction of apoptosis and influence on the cell cycle have also been carried out on other compounds, mainly synthesized by the Universities of Genoa and of Calabria (Rende – CS), as well as on some natural compounds such as Curcumin or compounds extracted from plants in Tunisia, in ‘field of scientific collaborations. Finally, the methods for modeling and simulations of docking of proteins and proteins: ligands have been implemented and optimized and have allowed us to publish numerous scientific articles in recent years. The skills acquired in this research area, together with the Mass Spectrometry activities and the acquisition of MALDI Imaging technology, will constitute the pillars on which to base the scientific production of the next three years.
Hypothesis and significance
We hypothesize that our Calixpirrole derivatives will be translated to clinical trials within the duration of the present research. We also believe we can help to synthesize novel molecules in collaboration with different National/International Institutions thanks to our skills on Computational biology and Bioinformatics techniques. Eventually, the success obtained by Allostatine, make us confident that its improved version “Evostatine” we are proposing as a novel Adjuvant for therapeutic vaccines, will have a strong impact on the health system
Significance and Innovation
The proposed research presents different novel approaches to a well-known problem such as Cancer. Among them the introduction of an innovative class of compounds such as Calix[n]pyrroles in Medicinal Chemistry. In our recent tests we proved this class possess all the characteristics to be considered as a first-class compound for NSCLC treatment due to their very low (or no-) acute toxicity, high efficacy in vivo and their property to be assembled as nanoparticles. Our skills in Computational Biology will allow a faster approach to the characterization of the novel drugs greatly reducing the need to test drugs on animals. Furthermore, Evostatine has the properties to booster Therapeutic Anticancer Vaccination. We believe this research represents a promising approach to tackle Cancer (in particular NSCLC) with personalized interventions, in a perspective of precision medicine.
Translational relevance and impact for the National Health System (SSN)
The achievement of the set objectives (or even only part of them) could lead to significant improvements in the therapy of various tumor and / or neurodegenerative pathologies. The complete molecular description of the studied proteins and of the protein: protein complexes will make possible the rational design of highly specific “molecular” drugs for the chosen target. The transport and controlled release of drugs either on site or directly on the diseased cells will allow the patient to avoid all those side effects typical of anticancer therapies and a better efficacy of the compounds used. The characterization of the molecular processes modulated by the compounds studied will allow to identify the target of choice for each molecule tested, thus allowing an optimization of the compounds themselves.
