Broad-spectrum coronavirus 3C-like protease peptidomimetic inhibitors effectively block SARS-CoV-2 replication in cells: Design, synthesis, biological evaluation, and X-ray structure determination

Despite the approval of vaccines, monoclonal antibodies and restrictions during the pandemic, the demand for new efficacious and safe antivirals is compelling to boost the therapeutic arsenal against the COVID-19. The viral 3-chymotrypsin-like protease (3CLpro) is an essential enzyme for replication with high homology in the active site across CoVs and variants showing an almost unique specificity for Leu-Gln as P2–P1 residues, allowing the development of broad-spectrum inhibitors. The design, synthesis, biological activity, and cocrystal structural information of newly conceived peptidomimetic covalent reversible inhibitors are herein described. The inhibitors display an aldehyde warhead, a Gln mimetic at P1 and modified P2–P3 residues. Particularly, functionalized proline residues were inserted at P2 to stabilize the β-turn like bioactive conformation, modulating the affinity. The most potent compounds displayed low/sub-nM potency against the 3CLpro of SARS-CoV-2 and MERS-CoV and inhibited viral replication of three human CoVs, i.e. SARS-CoV-2, MERS-CoV, and HCoV 229 in different cell lines. Particularly, derivative 12 exhibited nM-low μM antiviral activity depending on the virus, and the highest selectivity index. Some compounds were co-crystallized with SARS-CoV-2 3CLpro validating our design. Altogether, these results foster future work toward broad-spectrum 3CLpro inhibitors to challenge CoVs related pandemics

Atopic dermatitis

Atopic dermatitis (AD) is a common in ammatory skin disease, clinically characterized by recur- rent eczematous lesions and intense itching, leading to excoriations and susceptibility to cutaneous infections. Although it is considered a pediatric disorder, mainly starting in infancy, it is also very common in adults. Etiology of AD is complex and multifactorial: interaction between genetic susceptibility and environment, but also cutaneous barrier impairment, change in microbiome composition and innate and adaptive immune dysregulation are the main factors involved in the pathogenesis of the disease. Originally, the disorder was considered mediated by an imbalance towards a T-helper 2 response and excessive IgE production to aller- gens, but now it is recognized as a lifelong disposition with variable clinical expressivity, where dysfunctions of the epidermal barrier, immune system and microbiome play a central role. AD leads to a substantial psycho- social burden on patients and their relatives and increases the risk of other allergic and non allergic disorders. e real economic impact of AD is di cult to measure due to the broad spectrum of disease severity and the multiple direct and indirect costs, but the overall medical expenses seem to be very high and similar to those of other diseases such as diabetes. Currently, a multiple therapeutic approach is aimed only at improving the skin state, reducing itching and keeping a stable condition. New safety and curative treatments may be devel- oped only after enhancing our understanding on the pathogenesis of AD and the heterogeneity of its clinical manifestations. (www.actabiomedica.it

Structure-activity relationships, biological evaluation and structural studies of novel pyrrolonaphthoxazepines as antitumor agents

Microtubule-targeting agents (MTAs) are a class of clinically successful anti-cancer drugs. The emergence of multidrug resistance to MTAs imposes the need for developing new MTAs endowed with diverse mechanistic properties. Benzoxazepines were recently identified as a novel class of MTAs. These anticancer agents were thoroughly characterized for their antitumor activity, although, their exact mechanism of action remained elusive. Combining chemical, biochemical, cellular, bioinformatics and structural efforts we developed improved pyrrolonaphthoxazepines antitumor agents and their mode of action at the molecular level was elucidated. Compound 6j, one of the most potent analogues, was confirmed by X-ray as a colchicine-site MTA. A comprehensive structural investigation was performed for a complete elucidation of the structure-activity relationships. Selected pyrrolonaphthoxazepines were evaluated for their effects on cell cycle, apoptosis and differentiation in a variety of cancer cells, including multidrug resistant cell lines. Our results define compound 6j as a potentially useful optimized hit for the development of effective compounds for treating drug-resistant tumors.This work was supported in part by a grant from the Swiss National Science Foundation (31003A_166608; to M.O.S), grant BFU2016-75319-R (AEI/FEDER, EU) from Ministerio de Economia y Competitividad, Blueprint 282510, AIRC-17217. The authors acknowledge networking contribution by the COST Action CM1407 “Challenging organic syntheses inspired by nature - from natural products chemistry to drug discovery” (to M.O.S. and J.F.D.) and the COST Action EPICHEMBIO CM-1406 (to L.A. and G.C.). This work has also received partial funding from the European Union’s Horizon 2020 (EU) research and innovation programme under the Marie Sklodowska-Curie grant agreement No 721906. Finally, this work was partially funded by MIUR-PRIN project n. 2015Y3C5KP (to L.M.)

Optimization and Integration of Shape Memory Alloy (SMA)-Based Elastic Actuators within a Morphing Flap Architecture

Aircraft morphing architectures are currently worldwide investigated to enhance performance while reducing weights, volumes and costs. A 3-flap wing, for instance, shall pay a penalty up to 100% due to the insertion of mechanical devices in its body. Moreover, the insertion of cover nacelles disturbs the wing aerodynamics itself. In addition, flapped wings are noisy: deformable, instead of slotted and flapped wings, may lead to significant enhancement also in this field. Within Joint European Initiative on Green Regional Aircraft frame, in cooperation with the University of Naples, Department of Aerospace Engineering, the authors with their colleagues came to the definition of dedicated morphing architectures. This paper focuses on the design and optimization of a morphing architecture based on Shape Memory Alloy (SMA) technology, aimed at increasing airfoil trailing edge curvature. The deformable rib system is constituted of four elastic elements. The aerodynamic loads were computed through a classical panel method for the most severe flight condition. The descriptive finite element model underwent an optimization process performed through a proprietary code, based on a genetic selection strategy. Resulting values, from the optimization study were different for the variables referring to each subsystem: plate thickness, depth and length, relative orientation, SMA ribbons thickness, depth and location. Trailing edge vertical displacement was assumed as target. The main features of the 4 elastic elements are presented in the body of the document. As expected, the more rearward is the element position, the less is the weight and size; decreasing values of the aerodynamic load led towards lighter solutions

Car Soundproof Improvement through an SMA Adaptive System

The work at hand focuses on an adaptive system aimed at improving the soundproof performance of car door seals at specific regimes (cruise), without interfering with the conventional opening and closing operations. The idea addresses the necessity of increasing seal effectiveness, jeopardized by aerodynamic actions that strengthen as the speed increases, generating a growing pressure difference between the internal and the external field in the direction of opening the door, and then deteriorating the acoustic insulation. An original expansion mechanism driven by a shape memory alloy (SMA) wire was integrated within the seal cavity to reduce that effect. The smart material was activated (heated) by using the Joule effect; its compactness contributed to the realization of a highly-integrable and modular system (expanding cells). In this paper, the system development process is described together with the verification and validation activity, aimed at proving the functionality of the realized device. Starting from industrial requirements, a suitable solution was identified by considering the basic phenomenon principle and the allowable design parameters. The envisaged system was designed and its executive digital mock-up (CAD, computer-aided design) was released. Prototyping and laboratory tests showed the reliability of the developed numerical models and validated the associated predictions. Finally, the system was integrated within the reference car. To demonstrate the insulation effect, the experimental campaign was carried out in an anechoic room, achieving significant results on the concept value

A Preliminary Assessment of an FBG-Based Hard Landing Monitoring System

In aeronautics, hard landing is a critical condition as the aircraft approaches the runway with a vertical velocity that exceeds 2 m/s. Beyond that level, the energy that should be then absorbed by the whole structure could cause severe damage to the landing gear and the whole structural system. This document reports on the set-up, execution and results of a preparatory test campaign performed on a small landing gear (LG) demonstrator instrumented with a fibre-optic sensor system. In detail, a leaf spring landing gear was released from a drop tower to detect information about the strain state and the related acceleration history of some specific components during the impact. The objective of the present research is the development of a method for assessing whether hard landing is experienced, and to what extent. Deformation measurements through an integrated Fibre-Bragg Grating (FBG) network allowed retrieving impact velocity by a devoted, original algorithm. The proposed preliminary methodology is the base for assessing a more complex procedure to correlate structural response to the energy entering the structure during the touchdown event

Preliminary Assessment of an FBG-Based Landing Gear Weight on Wheel System

Weight-on-Wheels (WoW) systems are aimed at indicating if the aircraft weight is loading onto the landing gear and its wheels, even partially. These systems are an integral part of the actuation system for safety-critical applications and shall provide reliable information on the actual operational status of the LG. That information reveals if the vehicle is in flight or on the ground. In this way, several kinds of accidents may be prevented, relating for instance, to the incorrect deployment of the landing gear, or even manoeuvres to a certain extent, therefore protecting the aircraft from dangerous damage. There are different architectures that have been proposed in the bibliography, some of them based on strain gauges deployed on the structure, or on proximity sensors installed on the wheels. Being this device and considered critical for safety, it is convenient to couple it with complementary measurements, recorded and processed by different sources. In general, it can be stated that such an intelligent sensor network may be seen as a fundamental support for proper landing gear deployment. The presented paper reports the results of a preliminary investigation performed by the authors to evaluate the possibility of deploying fibre optics on the landing gear structure as part of a WoW system to retrieve the required information. This choice would have a remarkable effect in terms of significant cabling reduction (a single array of sensing elements could be deployed over a single line), and cost abatement from both a manufacturing and operational point of view. There are many other benefits also when referring to an optical instead of a standard electrical sensor system. Due to its small size and ease of integration into different families of materials, it could be considered a system for monitoring the operating status of most actuators on board modern aircraft

Preliminary Assessment of an FBG-Based Landing Gear Weight on Wheel System

Weight-on-Wheels (WoW) systems are aimed at indicating if the aircraft weight is loading onto the landing gear and its wheels, even partially. These systems are an integral part of the actuation system for safety-critical applications and shall provide reliable information on the actual operational status of the LG. That information reveals if the vehicle is in flight or on the ground. In this way, several kinds of accidents may be prevented, relating for instance, to the incorrect deployment of the landing gear, or even manoeuvres to a certain extent, therefore protecting the aircraft from dangerous damage. There are different architectures that have been proposed in the bibliography, some of them based on strain gauges deployed on the structure, or on proximity sensors installed on the wheels. Being this device and considered critical for safety, it is convenient to couple it with complementary measurements, recorded and processed by different sources. In general, it can be stated that such an intelligent sensor network may be seen as a fundamental support for proper landing gear deployment. The presented paper reports the results of a preliminary investigation performed by the authors to evaluate the possibility of deploying fibre optics on the landing gear structure as part of a WoW system to retrieve the required information. This choice would have a remarkable effect in terms of significant cabling reduction (a single array of sensing elements could be deployed over a single line), and cost abatement from both a manufacturing and operational point of view. There are many other benefits also when referring to an optical instead of a standard electrical sensor system. Due to its small size and ease of integration into different families of materials, it could be considered a system for monitoring the operating status of most actuators on board modern aircraft

Fiber Bragg Grating Bonding Characterization under Long-Period Cyclic Loading

The Smart Landing Gear system to be developed in the framework of the ANGELA project provides the strain measurements on landing gear structure at landings, and this system should be maintained efficiently under operational conditions. It is intended to assess the relevance of Fiber Bragg Gratings for in-flight testing. To assess the capabilities of the FBG bonding and to analyze the strain transmission conditions from the host structure to the FBG through the bonding layer during the operational phases of landing gears, a long-period cyclic loading test campaign on the bonding layer itself was performed. The primary objective of this fatigue-like test was to prove the ability of FBG sensors to withstand the operational life-cycle of landing gear while providing the same strain transfer function throughout the entire cycle; the secondary objective was to select the most suitable fiber-coating and bonding agents for this application. This document describes the execution and results of the fatigue-like test, intended as a preparatory test campaign to support the preliminary design activities of the Smart Landing System