Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appeared just over 7 months ago in Wuhan, China. Early reports from China indicated that although some cases are asymptomatic, 20% of COVID-19 cases follow a severe course, necessitating hospitalization, with a quarter of hospitalized patients requiring intensive care unit (ICU) facilities [1]. Later reports from China and other countries substantiated these data, although ICU admission rates, proportion of patients receiving invasive mechanical ventilation (IMV), and mortality rates differ considerably between studies [2]. The life-threatening form of respiratory failure, acute respiratory distress syndrome (ARDS) is a frequent complication in COVID-19 [3]. The severity of ARDS is classified into categories of mild, moderate, and severe, depending on the degree of hypoxemia [4]. Patients with moderate-tosevere ARDS require invasive mechanical ventilation (IMV) and have a poor prognosis [4]. The incidence of ARDS and specifically, moderate-to-severe ARDS, among COVID-19 patients is currently unknown [5]. We describe here the results of a survey of clinical studies reporting COVID-19-associated ARDS in hospitalized patients since the beginning of the COVID-19 pandemic in January until the end of July 2020. Our aim was to obtain a clearer picture of the incidence of COVID-19-associated ARDS in hospitalized patients on a global level, to better define the burden to healthcare
Numerous short peptides have been shown to form b-sheet amyloid aggregates in vitro.Proteins that contain such sequences are likely to be problematic for a cell, due to their potential to aggregate into toxic structures. We investigated the structures of 30 proteins containing 45 sequences known to form amyloid, to see how the proteins cope with the presence of these potentially toxic sequences, studying secondary structure, hydrogen-bonding, solvent accessible surface area and hydrophobicity. We identified two mechanisms by which proteins avoid aggregation: Firstly, amyloidogenic sequences are often found within helices, despite their inherent preference to form b structure. Helices may offer a selective advantage, since in order to form amyloid the sequence will presumably have to first unfold and then refold into a b structure. Secondly, amyloidogenic sequences that are found in b structure are usually buried within the protein. Surface exposed amyloidogenic sequences are not tolerated in strands, presumably because they lead to protein aggregation via assembly of the amyloidogenic regions. The use of a-helices, where amyloidogenic sequences are forced into helix, despite their intrinsic preference for b structure, is thus a widespread mechanism to avoid protein aggregation.
The amiloride-sensitive epithelial sodium channel (ENaC) plays a prominent role in sodium uptake from alveolar fluid, and is the major component in alveolar fluid clearance in normal and diseased lungs. The lectin-like domain of TNF-α has been shown to activate amiloride-sensitive sodium uptake in type II alveolar epithelial cells. Therefore, several synthetic peptides that mimic the lectin-like domain of TNF-α (TIP) were synthesised and their ability to enhance sodium current through ENaC was studied in A549 cells with the patch clamp technique. Our data suggest that a free positively-charged N-terminal amino group on residue 1 and/or a free negatively-charged carboxyl group on residue 17 of the TIP peptide is essential for the ENaC-activating effect. Ventilation strategies apart, no standard treatment exists for pulmonary permeability oedema. Therefore, novel therapies activating sodium uptake from the alveolar fluid via ENaC could improve clinical outcome.
AP301 [Cyclo(CGQRETPEGAEAKPWYC)], a cyclic peptide comprising the human tumor necrosis factor lectin-like domain (TIP domain) sequence, is currently being developed as a treatment for lung edema and has been shown to reduce extravascular lung water and improve lung function in mouse, rat, and pig models. The current paradigm for liquid homeostasis in the adult mammalian lung is that passive apical uptake of sodium via the amiloride-sensitive epithelial Na 1 channel (ENaC) and nonselective cyclic-nucleotide-gated cation channels creates the major driving force for reabsorption of water through the alveolar epithelium in addition to other ion channels such as potassium and chloride channels. AP301 can increase amiloride-sensitive current in A549 cells as well as in freshly isolated type II alveolar epithelial cells from different species. ENaC is expressed endogenously in all of these cell types. Consequently, this study was undertaken to determine whether ENaC is the specific target of AP301. The effect of AP301 in A549 cells as well as in human embryonic kidney cells and Chinese hamster ovary cells heterologously expressing human ENaC subunits (a, b, g, and d) was measured in patch clamp experiments. The congener TIP peptide AP318 [Cyclo(4-aminobutanoic acid-GQRETPEGAEAKPWYD)] activated ENaC by increasing single-channel open probability. AP301 increased current in proteolytically activated (cleaved) but not near-silent (uncleaved) ENaC in a reversible manner. abg-or dbg-ENaC coexpression was required for maximal activity. No increase in current was observed after deglycosylation of extracellular domains of ENaC. Thus, our data suggest that the specific interaction of AP301 with both endogenously and heterologously expressed ENaC requires precedent binding to glycosylated extracellular loop(s).
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