An overview of carbohydrate-based carbonic anhydrase inhibitors

Carbonic anhydrases (CAs) are metalloenzymes responsible for the reversible hydration of carbon dioxide to bicarbonate, a fundamental reaction involved in various physiological and pathological processes. In the last decades, CAs have been considered as important drug targets for different pathologies such as glaucoma, epilepsy and cancer. The design of potent and selective inhibitors has been an outstanding goal leading to the discovery of new drugs. Among the different strategies developed to date, the design of carbohydrate-based CA inhibitors (CAIs) has emerged as a versatile tool in order to selectively target CAs. The insertion of a glycosyl moiety as a hydrophilic tail in sulfonamide, sulfenamide, sulfamate or coumarin scaffolds allowed the discovery of many different series of sugar-based CAIs, with relevant inhibitory results. This review will focus on carbohydrate-based CAIs developed so far, classifying them in glycosidic and glycoconjugated inhibitors based on the conjugation chemistry adopted

Developments in carbohydrate-based metzincin inhibitors

Matrix metalloproteinases (MMPs) and A disintegrin and Metalloproteinase (ADAMs) are zinc-dependent endopeptidases belonging to the metzincin superfamily. Upregulation of metzincin activity is a major feature in many serious pathologies such as cancer, inflammations, and infections. In the last decades, many classes of small molecules have been developed directed to inhibit these enzymes. The principal shortcomings that have hindered clinical development of metzincin inhibitors are low selectivity for the target enzyme, poor water solubility, and long-term toxicity. Over the last 15 years, a novel approach to improve solubility and bioavailability of metzincin inhibitors has been the synthesis of carbohydrate-based compounds. This strategy consists of linking a hydrophilic sugar moiety to an aromatic lipophilic scaffold. This review aims to describe the development of sugar-based and azasugar-based derivatives as metzincin inhibitors and their activity in several pathological models

Selectively charged and zwitterionic analogues of the smallest immunogenic structure of Streptococcus pneumoniae type 14

Zwitterionic polysaccharides (ZPs) have been shown in recent years to display peculiar immunological properties, thus attracting the interest of the carbohydrate research community. To fully elucidate the mechanisms underlying these properties and exploit the potential of this kind of structures, in depth studies are still required. In this context, the preparation of two cationic, an anionic, as well as two zwitterionic tetrasaccharide analogues of the smallest immunogenic structure of Streptococcus pneumoniae type 14 (SP14) capsular polysaccharide are presented. By exploiting a block strategy, the negative charge has been installed on the non-reducing end of the lactose unit of the tetrasaccharide and the positive charge either on the non-reducing end of the lactosamine moiety or on an external linker. These structures have then been tested by competitive ELISA, showing that the structural variations we made do not modify the affinity of the neutral compound to binding to a specific antibody. However, lower efficacies than the natural SP14 compound were observed. The results obtained, although promising, point to the need to further elongate the polysaccharide structure, which is likely too short to cover the entire epitopes

Activation of carbonic anhydrases from human brain by amino alcohol oxime ethers: towards human carbonic anhydrase VII selective activators

The synthesis and carbonic anhydrase (CA; EC 4.2.1.1) activating effects of a series of oxime ether-based amino alcohols towards four human (h) CA isoforms expressed in human brain, hCA I, II, IV and VII, are described. Most investigated amino alcohol derivatives induced a consistent activation of the tested CAs, with KAs spanning from a low micromolar to a medium nanomolar range. Specifically, hCA II and VII, putative main CA targets when central nervous system (CNS) diseases are concerned, were most efficiently activated by these oxime ether derivatives. Furthermore, a multitude of selective hCA VII activators were identified. As hCA VII is one of the key isoforms involved in brain metabolism and other brain functions, the identified potent and selective hCA VII activators may be considered of interest for investigations of various therapeutic applications or as lead compounds in search of even more potent and selective CA activators

The metalloproteinase ADAM10 requires its activity to sustain surface expression

The metalloproteinase ADAM10 critically contributes to development, inflammation, and cancer and can be controlled by endogenous or synthetic inhibitors. Here, we demonstrate for the first time that loss of proteolytic activity of ADAM10 by either inhibition or loss of function mutations induces removal of the protease from the cell surface and the whole cell. This process is temperature dependent, restricted to mature ADAM10, and associated with an increased internalization, lysosomal degradation, and release of mature ADAM10 in extracellular vesicles. Recovery from this depletion requires de novo synthesis. Functionally, this is reflected by loss and recovery of ADAM10 substrate shedding. Finally, ADAM10 inhibition in mice reduces systemic ADAM10 levels in different tissues. Thus, ADAM10 activity is critically required for its surface expression in vitro and in vivo. These findings are crucial for development of therapeutic ADAM10 inhibition strategies and may showcase a novel, physiologically relevant mechanism of protease removal due to activity loss

An experimental study on latency-aware and self-adaptive service chaining orchestration in distributed NFV and SDN infrastructures

Network Function Virtualization (NFV) and Software Defined Networking (SDN) changed radically the way 5G networks will be deployed and services will be delivered to vertical applications (i.e., through dynamic chaining of virtualized functions deployed in distributed clouds to best address latency requirements). In this work, we present a service chaining orchestration system, namely LASH-5G, running on top of an experimental set-up that reproduces a typical 5G network deployment with virtualized functions in geographically distributed edge clouds. LASH-5G is built upon a joint integration effort among different orchestration solutions and cloud deployments and aims at providing latency-aware, adaptive and reliable service chaining orchestration across clouds and network resource domains interconnected through SDN. In this paper, we provide details on how this orchestration system has been deployed and it is operated on top of the experimentation infrastructure provided within the Fed4FIRE+ facility and we present performance results assessing the effectiveness of the proposed orchestration approach

Constraining Absolute Plate Motions Since the Triassic

The absolute motion of tectonic plates since Pangea can be derived from observations of hotspot trails, paleomagnetism, or seismic tomography. However, fitting observations is typically carried out in isolation without consideration for the fit to unused data or whether the resulting plate motions are geodynamically plausible. Through the joint evaluation of global hotspot track observations (for times <80 Ma), first‐order estimates of net lithospheric rotation (NLR), and parameter estimation for paleo–trench migration (TM), we present a suite of geodynamically consistent, data‐optimized global absolute reference frames from 220 Ma to the present. Each absolute plate motion (APM) model was evaluated against six published APM models, together incorporating the full range of primary data constraints. Model performance for published and new models was quantified through a standard statistical analyses using three key diagnostic global metrics: root‐mean square plate velocities, NLR characteristics, and TM behavior. Additionally, models were assessed for consistency with published global paleomagnetic data and for ages <80 Ma for predicted relative hotspot motion, track geometry, and time dependence. Optimized APM models demonstrated significantly improved global fit with geological and geophysical observations while performing consistently with geodynamic constraints. Critically, APM models derived by limiting average rates of NLR to ~0.05°/Myr and absolute TM velocities to ~27‐mm/year fit geological observations including hotspot tracks. This suggests that this range of NLR and TM estimates may be appropriate for Earth over the last 220 Myr, providing a key step toward the practical integration of numerical geodynamics into plate tectonic reconstructions

Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide

ADAMTS-5 is a major protease involved in the turnover of proteoglycans such as aggrecan and versican. Dysregulated aggrecanase activity of ADAMTS-5 has been directly linked to the etiology of osteoarthritis (OA). For this reason, ADAMTS-5 is a pharmaceutical target for the treatment of OA. ADAMTS-5 shares high structural and functional similarities with ADAMTS-4, which makes the design of selective inhibitors particularly challenging. Here we exploited the ADAMTS-5 binding capacity of β-N-acetyl-d-glucosamine to design a new class of sugar-based arylsulfonamides. Our most promising compound, 4b, is a non-zinc binding ADAMTS-5 inhibitor which showed high selectivity over ADAMTS-4. Docking calculations combined with molecular dynamics simulations demonstrated that 4b is a cross-domain inhibitor that targets the interface of the metalloproteinase and disintegrin-like domains. Furthermore, the interaction between 4b and the ADAMTS-5 Dis domain is mediated by hydrogen bonds between the sugar moiety and two lysine residues (K532 and K533). Targeted mutagenesis of these two residues confirmed their importance both for versicanase activity and inhibitor binding. This positively-charged cluster of ADAMTS-5 represents a previously unknown substrate-binding site (exosite) which is critical for substrate recognition and can therefore be targeted for the development of selective ADAMTS-5 inhibitors

The westward lithospheric drift, its role on the subduction and transform zones surrounding Americas: Andean to Cordilleran orogenic types cyclicity

We investigate the effect of the westerly rotation of the lithosphere on the active margins that surround the Americas and find good correlations between the inferred easterly-directed mantle counterflow and the main structural grain and kinematics of the Andes and Sandwich arc slabs. In the Andes, the subduction zone is shallow and with low dip, because the mantle flow sustains the slab; the subduction hinge converges relative to the upper plate and generates an uplifting doubly verging orogen. The Sandwich Arc is generated by a westerly-directed SAM (South American) plate subduction where the eastward mantle flow is steepening and retreating the subduction zone. In this context, the slab hinge is retreating relative to the upper plate, generating the backarc basin and a low bathymetry single-verging accretionary prism. In Central America, the Caribbean plate presents a more complex scenario: (a) To the East, the Antilles Arc is generated by westerly directed subduction of the SAM plate, where the eastward mantle flow is steepening and retreating the subduction zone. (b) To the West, the Middle America Trench and Arc are generated by the easterly-directed subduction of the Cocos plate, where the shallow subduction caused by eastward mantle flow in its northern segment gradually steepens to the southern segment as it is infered by the preexisting westerly-directed subduction of the Caribbean Plateau.In the frame of the westerly lithospheric flow, the subduction of a divergent active ridge plays the role of introducing a change in the oceanic/continental plate's convergence angle, such as in NAM (North American) plate with the collision with the Pacific/Farallon active ridge in the Neogene (Cordilleran orogenic type scenario). The easterly mantle drift sustains strong plate coupling along NAM, showing at Juan de Fuca easterly subducting microplate that the subduction hinge advances relative to the upper plate. This lower/upper plate convergence coupling also applies along strike to the neighbor continental strike slip fault systems where subduction was terminated (San Andreas and Queen Charlotte). The lower/upper plate convergence coupling enables the capture of the continental plate ribbons of Baja California and Yakutat terrane by the Pacific oceanic plate, transporting them along the strike slip fault systems as para-autochthonous terranes. This Cordilleran orogenic type scenario, is also recorded in SAM following the collision with the Aluk/Farallon active ridge in the Paleogene, segmenting SAM margin into the eastwardly subducting Tupac Amaru microplate intercalated between the proto-Liquiñe-Ofqui and Atacama strike slip fault systems, where subduction was terminated and para-autochthonous terranes transported. In the Neogene, the convergence of Nazca plate with respect to SAM reinstalls subduction and the present Andean orogenic type scenario