"Network Medicine and Drug Repurposing Network Medicine and Drug Repurposing" Prof. Joseph Loscalzo, MD, PhD (Brigham and Women’s Hospital Harvard Medical School, Boston, Massachusetts)
27/10/2022
Conventional drug discovery requires identifying a protein target believed to be important for
disease mechanism and screening compounds for those that beneficially alter the target’s function.
While this approach has been an effective one for decades, recent data suggest that its continued
success is limited largely owing to the essential irreducibility of biologically complex systems that
govern disease phenotype to a single primary disease driver. Moreover, bioinformatic analysis
suggests that each approved drug can theoretically bind to ~32 targets, supporting the notion that
many existing drugs can be repurposed for the treatment of (many) other diseases. Network
medicine, a new discipline that applies network science and systems biology to the analysis of
complex biological systems and disease, offers a novel approach to overcoming these limitations of
conventional drug discovery, and dissecting the complexity implicit in the pluripotency of many drug
compounds. Using the comprehensive protein-protein interaction network (interactome) as the
template through which subnetworks that govern specific diseases are identified; potential disease
drivers are unveiled; and the effect of repurposed drugs, identified from network features,
physicochemical compound features, and machine learning- and artificial intelligence-based
analyses, are studied. This approach to drug discovery offers new and exciting unbiased
possibilities for advancing our knowledge of disease mechanisms and precision therapeutics.
|
"The Chemical Complexity of Food: A Network Science Approach”, Prof. Joseph Loscalzo, MD, PhD (Brigham and Women’s Hospital Harvard Medical School, Boston, Massachusetts)
24/10/2022
The food supply offers a rich panoply of (bio)chemical compounds that affect biological function.
While the latest data suggest that there are over 135,000 compounds in the food supply, knowledge
of their relationship to (patho)biological phenotype is rather limited, with a mere ~200 having been
studied epidemiologically and/or functionally. This ‘dark matter’ of nutrition offers a stunning
opportunity to explore the normal biochemical functions of food compounds, as well as their
potential role as drugs. Using a combination of machine learning, artificial intelligence, network
medicine, epidemiological association, and cell-based experimentation, we demonstrate an effective
approach to dissecting the functional richness of (bio)chemicals in the food supply, and their
potential application to health and disease.
|
"Optimizing Drug-Target Interactions: Challenges and Opportunities”, Prof. Joseph Loscalzo, Brigham and Women’s Hospital Harvard Medical School, Boston, Massachusetts
20/10/2022
The development of drug therapies holds many challenges beyond the synthesis of the drug. For example, diffusion of drug compounds
through the macromolecule-rich cytoplasm to their specific targets is a complicated process that does not follow conventional laws of
diffusion. Drug diffusion in the cytosol is anomalous, owing to low(er) affinity, high capacity interactions with other (macro)molecular species
in the cell, resulting in quite different binding interactions and kinetic constants than predicted from isolated studies of the drug and its
purified target in dilute solution. Here, we present data supporting these anomalous behaviors, and illustrate their consequences for
expected drug effects in vivo. Yet another challenge to optimizing effective drug-target interactions arises in studies of combination drug
therapies, where screening becomes exponentially more complicated as the number of drugs in the combination increases. With
personalized medicine requiring tailored combination therapies in many diseases for optimal efficacy, this important problem warrants novel
solutions. Here, we demonstrate a novel convection gradient approach to analyzing combination drug therapies in a system in which the
uptake and effect of bar-coded drugs over a range of concentrations are monitored in single cells, dramatically reducing the screening time
and experimental resources required for studying a wide range of concentrations and combinations. Lastly, the power of the placebo effect
in mitigating the measured efficacy of a drug in vivo presents another major challenge to optimizing drug development. Our work involving
molecular (protein-protein) interaction networks has given us new insight into the placebo effect and shown that it has a molecular basis that
can be understood and therapeutically exploited in many diseases.
|
Allosteric Regulation of Protein Kinases, Prof. Giuseppe Melacini, McMaster University Dept. of Chemistry & Chemical Biology Dept. of Biochemistry & Biomedical Sciences
12/10/2022
The potential of protein kinases as drug targets for a wide range of diseases is now well established. However, targeting kinases directly through competitive inhibitors poses a major selectivity challenge, as kinase active sites are typically quite conserved. A promising alternative strategy to inhibit kinases with enhanced selectivity relies on allosteric modulation. However, it is unclear how kinases integrate multiple concurrent allosteric signals and how protein dynamics influence the potencies and efficacies of allosteric drug leads. We will present our attempts to answer these fundamental questions for prototypical kinases.
|
Hyphenated analytical protocols for complex matrices investigation, Prof. Aura Tintaru Centre Interdisciplinaire de Nanoscience de Marseille, Aix-Marseille University (France)
05/07/2022
In order to overcome several technical limitations, combined approaches between Nuclear Magnetic Resonances (NMR) and Mass Spectrometry techniques (MS) have been set to study natural mixtures from plants (essential oils, etheric extracts etc.) with a high potential biological value. Examples of new methodological protocols NMR - MS/MS and NMR-IMS-MS will be described and largely discussed.
|
Ion mobility mass spectrometry - theory and applications. Prof. Aura Tintaru Centre Interdisciplinaire de Nanoscience de Marseille, Aix-Marseille University (France)
27/06/2022
In the last decade, ion mobility mass spectrometry (IM-MS) emerged as an alternative separation technique hyphenating gas phase diffusion processes to MS principles. The course content will be focalized on the general principals, instrumentation, data treatment and interpretation of IM-MS. To better illustrate the theoretical part, examples of different application will be also presented.
|
"La frazione volatile di una matrice vegetale: una miniera di informazioni ancora oggi sottostimata e di opportunità diagnostiche nella ricerca applicata”, Prof. Carlo Bicchi, Laboratorio of Biologia Farmaceutica e Chimica degli Alimenti, Dipartimento di Scienza e Tecnologia del Farmaco Università di Torino
22/06/2022
In termini biologici la frazione volatile emessa da una pianta è un importante biosensore,
diagnostico delle variazioni che hanno luogo nel suo metabolismo. In termini chimici la frazione
volatile è una miscela di composti che possono essere campionati come conseguenza della loro
capacità di essere vaporizzati sia spontaneamente che mediante opportune condizioni operative
o tecniche di campionamento. La combinazione del significato biologico e chimico della frazione
volatile è fondamentale per comprendere sia i fenomeni biologici complessi che le
caratteristiche di matrici di interesse alimentare, cosmetico e farmaceutico, o ancora per
monitorare importanti processi industriali. Sulla base di alcuni esempi che coinvolgono matrici
vegetali di natura completamente diversa e di applicazioni a problemi molto differenti, questo
seminario ha lo scopo di illustrare il ruolo della frazione volatile nella ricerca delle cosiddette
“informazioni di livello superiore”, ed al tempo stesso di descrivere le moderne strategie di
analisi chimica da adottate per questi studi.
|
Masitinib, Onpattro, and Beyond: the Central Role of Synthetic Organic Chemistry, Prof. Marco Ciufolini
21/06/2022
This presentation is directed toward a general audience, and thus it eschews specialist
details of how and why molecular targets are selected and synthesized. Instead, it
illustrates how curiosity-driven research in synthetic organic chemistry has inspired
solutions to biomedical problems in the fields of degenerative, proliferative and
infectious disease, nucleic acid therapeutics, cardiovascular health, and so on. In
particular, it outlines how research on the synthesis of thiopeptide natural products
enabled the development of new kinase inhibitors, cytotoxic agents, and anti-infective
resources; how synthetic work on mitomycinoids and tetrodotoxin inspired the quantum
leap that launched the field of nucleic acid therapeutics; and how a synthetic organic
culture plays a central role in the development of the medicines of the future.
|
Tandem Mass Spectrometry for peptides sequencing, Prof. Aura Tintaru Centre Interdisciplinaire de Nanoscience de Marseille, Aix-Marseille University (France)
20/06/2022
Electrospray (ESI) is a soft ionization technique largely used for biological sample analysis. ESI-Tandem mass spectrometry (ESI-MS/MS) offers an alternative way for sequencing. For a better understanding, the teaching activity start with an introduction to electrospray ionization technique and collision - induced dissociation. In the second time, it will provide the detailed description of peptides fragmentation rules as read from ESI-MS/MS. To better illustrate the theoretical part, several application exercises will be included.
|
Analytical protocols for the determination of contaminants on food matrices, rof. Lara Manyes i Font, Department of Preventive Medicine and Public Health, Food Science, Toxicology and Forensic Medicine. Universitat de València (Spain)
13/06-17/06
Practical course that involves a project proposal (report and oral
presentation) to set up a laboratory specialized in analyzing a type
of contaminants in a specific food matrix for research purposes.
Topics of choice:
1. Mycotoxins in bread
2. Pesticides in fresh fruits and vegetables
3. Antibiotics in pig meat
4. Bacteria in poultry meat
5. Parasites in mollusks
6. Virus in bottled water
7. Heavy metals in fish
8. Hormones in milk
|
|