Targeted Protein Degradation for Infectious Diseases: from Basic Biology to Drug Discovery

Targeted protein degradation (TPD) is emerging as one of the most innovative strategies to tackle infectious diseases. Particularly, proteolysis-targeting chimera (PROTAC)-mediated protein degradation may offer several benefits over classical anti-infective small-molecule drugs. Because of their peculiar and catalytic mechanism of action, anti-infective PROTACs might be advantageous in terms of efficacy, toxicity, and selectivity. Importantly, PROTACs may also overcome the emergence of antimicrobial resistance. Furthermore, anti-infective PROTACs might have the potential to (i) modulate "undruggable"targets, (ii) "recycle"inhibitors from classical drug discovery approaches, and (iii) open new scenarios for combination therapies. Here, we try to address these points by discussing selected case studies of antiviral PROTACs and the first-in-class antibacterial PROTACs. Finally, we discuss how the field of PROTAC-mediated TPD might be exploited in parasitic diseases. Since no antiparasitic PROTAC has been reported yet, we also describe the parasite proteasome system. While in its infancy and with many challenges ahead, we hope that PROTAC-mediated protein degradation for infectious diseases may lead to the development of next-generation anti-infective drugs

From Monoamine Oxidase Inhibition to Antiproliferative Activity: New Biological Perspectives for Polyamine Analogs

Monoamine oxidases (MAOs) are well-known pharmacological targets in neurological and neurodegenerative diseases. However, recent studies have revealed a new role for MAOs in certain types of cancer such as glioblastoma and prostate cancer, in which they have been found overexpressed. This finding is opening new frontiers for MAO inhibitors as potential antiproliferative agents. In light of our previous studies demonstrating how a polyamine scaffold can act as MAO inhibitor, our aim was to search for novel analogs with greater inhibitory potency for human MAOs and possibly with antiproliferative activity. A small in-house library of polyamine analogs (2-7) was selected to investigate the effect of constrained linkers between the inner amine functions of a polyamine backbone on the inhibitory potency. Compounds 4 and 5, characterized by a dianiline (4) or dianilide (5) moiety, emerged as the most potent, reversible, and mainly competitive MAO inhibitors (Ki < 1 μM). Additionally, they exhibited a high antiproliferative activity in the LN-229 human glioblastoma cell line (GI50 < 1 μM). The scaffold of compound 5 could represent a potential starting point for future development of anticancer agents endowed with MAO inhibitory activity

A Complete Meteo/Hydro/Hydraulic Chain Application to Support Early Warning and Monitoring Systems: The Apollo Medicane Use Case

Because of the ongoing changing climate, extreme rainfall events’ frequency at the global scale is expected to increase, thus resulting in high social and economic impacts. A Meteo/Hydro/Hydraulic forecasting chain combining heterogeneous observational data sources is a crucial component for an Early Warning System and is a fundamental asset for Civil Protection Authorities to correctly predict these events, their effects, and put in place anticipatory actions. During the last week of October 2021 an intense Mediterranean hurricane (Apollo) affected many Mediterranean countries (Tunisia, Algeria, Malta, and Italy) with a death toll of seven people. The CIMA Meteo/Hydro/Hydraulic forecasting chain, including the WRF model, the hydrological model Continuum, the automatic system for water detection (AUTOWADE), and the hydraulic model TELEMAC-2D, was operated in real-time to predict the Apollo weather evolution as well as its hydrological and hydraulic impacts, in support of the early warning activities of the Italian Civil Protection Department. The WRF model assimilating radar data and in situ weather stations showed very good predictive capability for rainfall timing and location over eastern Sicily, thus supporting accurate river flow peak forecasting with the hydrological model Continuum. Based on WRF predictions, the daily automatic system for water detection (AUTOWADE) run using Sentinel 1 data was anticipated with respect to the scheduled timing to quickly produce a flood monitoring map. Ad hoc tasking of the COSMO-SkyMed satellite constellation was also performed to overcome the S1 data latency in eastern Sicily. The resulting automated operational mapping of floods and inland waters was integrated with the subsequent execution of the hydraulic model TELEMAC-2D to have a complete representation of the flooded area with water depth and water velocity

Transglutaminases, neuronal cell death and neural repair: Implications for traumatic brain injury and therapeutics

Purpose of review Traumatic brain injury (TBI) is one of the leading causes of death in the developed world. Despite advances at the bedside, pharmacological interventions have yet to be successful likely because of the need for a better understanding of disease mechanisms as potential targets for intervention. Recent evidence implicates a family of enzymes, namely transglutaminases, in the pathological mechanisms of TBI. Recent findings Transglutaminases are multifunctional, calcium-dependent enzymes that are significantly upregulated in TBI. They are known for their transamidase activity that consists of the covalent crosslinking of glutamines and lysines. Recent data support their ability to aminylate proteins with primary amines such as polyamines or monoamines like serotonin and histamine and to regulate gene transcription. Summary In this review, we will discuss data that support a role for transglutaminases, in particular transglutaminase 2, in mitochondrial damage, excitotoxicity and inflammation and their relationship to the pathobiology of TBI. We will review past evidence and outline the need for new experiments that could clarify the role of these enzymes in cell injury and death associated with traumatic brain injury

COMPOSTI ISOTIOCIANATI E ISOSELENCIANATI

La presente invenzione attiene una nuova famiglia di composti isotiocianati e isoselencianati idonei ad essere utilizzati come: - farmaci innovativi con spiccato profilo di efficacia terapeutica, tali da consentire un miglior approccio alla patologia tumorale rispetto ai farmaci attuali, - teranostici per la contemporanea diagnosi e cura della patologia oncologica; - sonde fluorescenti per l'osservazione diretta di specifici organuli cellulari in applicazioni biomediche

Sensitivity experiments of a severe rainfall event in north-western Italy: 17 August 2006

This study is embedded into a wider project named "Tackle deficiencies in Quantitative Precipitation Forecast (QPF)'' in the framework of the COSMO (<b>CO</b>nsortium for <b>S</b>mall-scale <b>MO</b>delling) community. In fact QPF is an important purpose of a numerical weather prediction model, for forecasters and customers. Unfortunately, precipitation is also a very difficult parameter to forecast quantitatively. This priority project aims at looking into the COSMO Model deficiencies concerning QPF by running different numerical simulations of various events not correctly predicted by the model. In particular, this work refers to a severe event (moist convection) happened in Piemonte region during summer 2006. On one side the results suggest that details in orography representation have a strong influence on accuracy of QPF. On the other side COSMO Model exhibits a poor sensitivity on changes in numerical and physical settings when measured in terms of QPF improvements. The conclusions, although not too general, give some hint towards the behaviour of the COSMO Model in a typical convective situation

Isothiocyanate synthetic analogs: biological activities, structure-activity relationships and synthetic strategies.

Sulforaphane is a natural product that is constantly under biological investigation for its unique biological properties. This naturally occurring isothiocyanate (ITC) and its analogs are the main components of cruciferous vegetables, such as cauliflower, watercress, broccoli, cabbage, Brussels sprouts, widely used as chemopreventive agents. Due to their interesting biological profiles, natural ITCs have been exploited as starting point to develop new synthetic analogs. The present mini-review briefly highlights the most important biological actions of selected new synthetic ITCs focusing on their structure-activity relationships and related synthetic strategies