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The astacin protease Meprin v represents an emerging target for drug development due to its potential involvement in disorders such as acute and chronic kidney injury and fibrosis. Here, we elaborate on the structural basis of inhibition by a specific Meprin v inhibitor. Our analysis of the crystal structure suggests different binding modes of the inhibitor to the active site. This flexibility is caused, at least in part, by movement of the C-terminal region of the protease domain (CTD). The CTD movement narrows the active site cleft upon inhibitor binding. Compared with other astacin proteases, among these the highly homologous isoenzyme Meprin a, differences in the subsites account for the unique selectivity of the inhibitor. Although the inhibitor shows substantial flexibility in orientation within the active site, the structural data as well as binding analyses, including molecular dynamics simulations, support a contribution of electrostatic interactions, presumably by arginine residues, to binding and specificity. Collectively, the results presented here and previously support an induced fit and substantial movement of the CTD upon ligand binding and, possibly, during catalysis. To the best of our knowledge, we here present the first structure of a Meprin v holoenzyme containing a zinc ion and a specific inhibitor bound to the active site. The structural data will guide rational drug design and the discovery of highly potent Meprin inhibitors.

Vorgeschichte: Die 30-jährige vorher immer gesunde Frau erleidet Anfang 2019 nach Kinderwunschbehandlung mit Clomifen einen Frühabort. Leitsymptom bei Krankheitsmanifestation: Im April 2019 erscheinen erstmalig Ekzem-artige, juckende Effloreszenzen am Stamm und im August 2019 kommt es zusätzlich[zum vollständigen Text gelangen Sie über die oben angegebene URL], Deutscher Rheumatologiekongress 2020, 48. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh), 34. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh)

Background and aims: Management of familial hypercholesterolaemia (FH) may vary across different settings due to factors related to population characteristics, practice, resources and/or policies. We conducted a survey among the worldwide network of EAS FHSC Lead Investigators to provide an overview of FH status in different countries. Methods: Lead Investigators from countries formally involved in the EAS FHSC by mid-May 2018 were invited to provide a brief report on FH status in their countries, including available information, programmes, initiatives, and management. Results: 63 countries provided reports. Data on FH prevalence are lacking in most countries. Where available, data tend to align with recent estimates, suggesting a higher frequency than that traditionally considered. Low rates of FH detection are reported across all regions. National registries and education programmes to improve FH awareness/knowledge are a recognised priority, but funding is often lacking. In most countries, diagnosis primarily relies on the Dutch Lipid Clinics Network criteria. Although available in many countries, genetic testing is not widely implemented (frequent cost issues). There are only a few national official government programmes for FH. Under-treatment is an issue. FH therapy is not universally reimbursed. PCSK9-inhibitors are available in ∼2/3 countries. Lipoprotein-apheresis is offered in ∼60% countries, although access is limited. Conclusions: FH is a recognised public health concern. Management varies widely across countries, with overall suboptimal identification and under-treatment. Efforts and initiatives to improve FH knowledge and management are underway, including development of national registries, but support, particularly from health authorities, and better funding are greatly needed. © 2018 Elsevier B.V.

Numerous studies suggest that the majority of amyloid-v (Av) peptides deposited in Alzheimer's disease (AD) are truncated and post-translationally modified at the N terminus. Among these modified species, pyroglutamyl-Av (pE-Av, including N3pE-Av40/42 and N11pE-Av40/42) has been identified as particularly neurotoxic. The N-terminal modification renders the peptide hydrophobic, accelerates formation of oligomers, and reduces degradation by peptidases, leading ultimately to the accumulation of the peptide and progression of AD. It has been shown that the formation of pyroglutamyl residues is catalyzed by glutaminyl cyclase (QC). Here, we present data about the pharmacological in vitro and in vivo efficacy of the QC inhibitor (S)-1-(1H-benzo[d]imidazol-5-yl)-5-(4-propoxyphenyl)imidazolidin-2-one (PQ912), the first-in-class compound that is in clinical development. PQ912 inhibits human, rat, and mouse QC activity, with Ki values ranging between 20 and 65 nM. Chronic oral treatment of hAPPSLxhQC double-transgenic mice with approximately 200 mg/kg/day via chow shows a significant reduction of pE-Av levels and concomitant improvement of spatial learning in a Morris water maze test paradigm. This dose results in a brain and cerebrospinal fluid concentration of PQ912 which relates to a QC target occupancy of about 60%. Thus, we conclude that >50% inhibition of QC activity in the brain leads to robust treatment effects. Secondary pharmacology experiments in mice indicate a fairly large potency difference for Av cyclization compared with cyclization of physiologic substrates, suggesting a robust therapeutic window in humans. This information constitutes an important translational guidance for predicting the therapeutic dose range in clinical studies with PQ912.

Alzheimer disease is associated with deposition of the amyloidogenic peptide A in the brain. Passive immunization using A-specific antibodies has been demonstrated to reduce amyloid deposition both in vitro and in vivo. Because N-terminally truncated pyroglutamate (pE)-modified A species (A(pE3)) exhibit enhanced aggregation potential and propensity to form toxic oligomers, they represent particularly attractive targets for antibody therapy. Here we present three separate monoclonal antibodies that specifically recognize A(pE3) with affinities of 1-10 nm and inhibit A(pE3) fibril formation in vitro. In vivo application of one of these resulted in improved memory in A(pE3) oligomer-treated mice. Crystal structures of F-ab-A(pE3) complexes revealed two distinct binding modes for the peptide. Juxtaposition of pyroglutamate pE3 and the F4 side chain (the pEF head) confers a pronounced bulky hydrophobic nature to the A(pE3) N terminus that might explain the enhanced aggregation properties of the modified peptide. The deep burial of the pEF head by two of the antibodies explains their high target specificity and low cross-reactivity, making them promising candidates for the development of clinical antibodies.

Zu den neurokognitiven Störungen gehören auch altersassoziierte Abbauprozesse kognitiver Funktionen, die sich als leichtes demenzielles Syndrom bzw. leichte kognitive Beeinträchtigung (mild cognitive impairment, MCI) manifestieren können. Mit diesen Abbauprozessen auf der Verhaltensebene sind degenerative Prozesse auf neuronaler Ebene eng verknüpft. Wichtiger Marker der Neurodegeneration sind unteranderem extrazellulare Ablagerungen Beta-Amyloider Plaques. Jedoch wurden trotz hoher Abeta-Pathologie nicht immer entsprechende kognitive Beeinträchtigungen beobachtet. Hier wird seit längerem eine kompensatorische Wirkung der prämorbiden kognitiven Leistungsfähigkeit im Sinne einer Reservefähigkeit diskutiert. In unserer Studie wurden 140 Probanden einem umfangreichen neuropsychologischen Screening unterzogen und Blutkonzentration von Amyloid-beta (As40, As42) bestimmt. Das kognitive Leistungsniveau, insbesondere Leistungen in Lern- und Gedächtnistests, korrelierte hoch mit einer Ratio aus As40 und As42. Diese Ratio wurde schon in anderen Studien als leistungsfähiger Biomarker der Neurodegeneration identifiziert. Bedeutsam war jedoch ein Moderatoreffekt der kognitiven Reservefunktionen, insbesondere geschätzt über das prämorbide Intelligenzniveaus. Es zeigte sich, dass Personen mit niedrigem prämorbiden Niveau bereits bei geringer As40/As42-Konzentration deutliche Gedächtnisdefizite aufweisen. Personen mit höherem prämorbiden Niveau erreichen bei vergleichbaren Konzentrationen altersentsprechende Gedächtnisleistungen. Jedoch treten mit steigenden As-Konzentrationen auch bei diesen Patienten die kognitiven Defizite auf. Unsere Ergebnisse zeigen deutlich das Personen, trotz vorliegender Neuropathologie, normale kognitive Leistungen erbringen können, wenn sie über entsprechende Reservefunktionen zur Kompensation verfügen. Diese Reservefunktionen sind stark vom Bildungsgrad und Intelligenzniveau abhängig. In der Diagnostik und Frühintervention ist auf diese Patienten ein besonderes Augenmerk zurichten, da bereits gering gradige kognitive Veränderungen auf fortgeschrittene neurodegenerative Prozesse hinweisen können.