Pentosan Polysulfate Inhibits Attachment and Infection by SARS-CoV-2 In Vitro: Insights into Structural Requirements for Binding

Two years since the outbreak of the novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic, there remain few clinically effective drugs to complement vaccines. One is the anticoagulant, heparin, which in 2004 was found able to inhibit invasion of SARS-CoV (CoV-1) and which has been employed during the current pandemic to prevent thromboembolic complications and moderate potentially damaging inflammation. Heparin has also been shown experimentally to inhibit SARS-CoV-2 attachment and infection in susceptible cells. At high therapeutic doses however, heparin increases the risk of bleeding and prolonged use can cause heparin-induced thrombocytopenia, a serious side effect. One alternative, with structural similarities to heparin, is the plant-derived, semi-synthetic polysaccharide, pentosan polysulfate (PPS). PPS is an established drug for the oral treatment of interstitial cystitis, is well-tolerated, and exhibits weaker anticoagulant effects than heparin. In an established Vero cell model, PPS and its fractions of varying molecular weights inhibited invasion by SARS-CoV-2. Intact PPS and its size-defined fractions were characterized by molecular weight distribution and chemical structure using nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry, then employed to explore the structural basis of interactions with SARS-CoV-2 spike protein receptor-binding domain (S1 RBD) and the inhibition of Vero cell invasion. PPS was as effective as unfractionated heparin, but more effective in inhibiting cell infection than low-molecular-weight heparin (on a weight/volume basis). Isothermal titration calorimetry and viral plaque-forming assays demonstrated size-dependent binding to S1 RBD and inhibition of Vero cell invasion, suggesting the potential application of PPS as a novel inhibitor of SARS-CoV-2 infection

Visible-light-induced, Ir-catalyzed reactions of N-methyl-N-((trimethylsilyl)methyl)aniline with cyclic α,β-unsaturated carbonyl compounds

N-Methyl-N-((trimethylsilyl)methyl)aniline was employed as reagent in visible-light-induced, iridium-catalyzed addition reactions to cyclic α,β-unsaturated carbonyl compounds. Typical reaction conditions included the use of one equivalent of the reaction substrate, 1.5 equivalents of the aniline and 2.5 mol % (in MeOH) or 1.0 mol % (in CH2Cl2) [Ir(ppy)2(dtbbpy)]BF4 as the catalyst. Two major reaction products were obtained in combined yields of 30–67%. One product resulted from aminomethyl radical addition, the other product was a tricyclic compound, which is likely formed by attack of the intermediately formed α-carbonyl radical at the phenyl ring. For five-membered α,β-unsaturated lactone and lactam substrates, the latter products were the only products isolated. For the six-membered lactones and lactams and for cyclopentenone the simple addition products prevailed

Visible-light-induced, Ir-catalyzed reactions of N-methyl-N-((trimethylsilyl)methyl)aniline with cyclic α,β-unsaturated carbonyl compounds

Abstract aniline was employed as reagent in visible-light-induced, iridium-catalyzed addition reactions to cyclic α,β-unsaturated carbonyl compounds. Typical reaction conditions included the use of one equivalent of the reaction substrate, 1.5 equivalents of the aniline and 2.5 mol % (in MeOH) or 1.0 mol % (in CH 2 Cl 2 ) [Ir(ppy) 2 (dtbbpy)]BF 4 as the catalyst. Two major reaction products were obtained in combined yields of 30-67%. One product resulted from aminomethyl radical addition, the other product was a tricyclic compound, which is likely formed by attack of the intermediately formed α-carbonyl radical at the phenyl ring. For five-membered α,β-unsaturated lactone and lactam substrates, the latter products were the only products isolated. For the six-membered lactones and lactams and for cyclopentenone the simple addition products prevailed. 89

Analysis of Image Sequences for the Detection and Monitoring of Moving Traffic

Analyse von Bildsequenzen zur Detektion und Überwachung von fließendem Verkehr. Dieser Artikel zielt auf das Erkennen und Verfolgen von Fahrzeugen aus luftgetragenen Bildsequenzen zur Überwachung von fließendem Verkehr. Zwei unterschiedliche Systeme werden beschrieben: Das Erste ist ein echtzeitnahes Tracking- Verfahren, welches auf der normalisierten Kreuzkorrelation basiert. Das zweite Verfahren bindet Modellwissen über Fahrerverhalten, Verkehrsdynamiken und Kontext ein, um Geschwindigkeitsund Trajektorienbewertungen auszunutzen. Die Ergebnisse und die abgeleiteten Qualitätsmaße zeigen die Leistungsfähigkeit der Systeme, insbesondere der Beitrag des Verkehrsmodellwissens erhöht die Korrektheit der Trackingergebnisse. Abschließend wird ein Ausblick auf zukünftige Forschungen gegeben

Structure-activity relationship in pyrazolo[4,3-c]pyridines, first inhibitors of PEX14-PEX5 protein-protein interaction with trypanocidal activity

Trypanosoma; protists are pathogens leading to a spectrum of devastating infectious diseases. The range of available chemotherapeutics against; Trypanosoma; is limited, and the existing therapies are partially ineffective and cause serious adverse effects. Formation of the PEX14-PEX5 complex is essential for protein import into the parasites' glycosomes. This transport is critical for parasite metabolism and failure leads to mislocalization of glycosomal enzymes, with fatal consequences for the parasite. Hence, inhibiting the PEX14-PEX5 protein-protein interaction (PPI) is an attractive way to affect multiple metabolic pathways. Herein, we have used structure-guided computational screening and optimization to develop the first line of compounds that inhibit PEX14-PEX5 PPI. The optimization was driven by several X-ray structures, NMR binding data, and molecular dynamics simulations. Importantly, the developed compounds show significant cellular activity against; Trypanosoma; , including the human pathogen; Trypanosoma brucei gambiense; and; Trypanosoma cruzi; parasites