Dissection of the amyloid formation pathway in AL amyloidosis

In antibody light chain (AL) amyloidosis, overproduced light chain (LC) fragments accumulate as fibrils in organs and tissues of patients. In vitro, AL fibril formation is a slow process, characterized by a pronounced lag phase. The events occurring during this lag phase are largely unknown. We have dissected the lag phase of a patient-derived LC truncation and identified structural transitions that precede fibril formation. The process starts with partial unfolding of the V-L domain and the formation of small amounts of dimers. This is a prerequisite for the formation of an ensemble of oligomers, which are the precursors of fibrils. During oligomerization, the hydrophobic core of the LC domain rearranges which leads to changes in solvent accessibility and rigidity. Structural transitions from an anti-parallel to a parallel beta-sheet secondary structure occur in the oligomers prior to amyloid formation. Together, our results reveal a rate-limiting multi-step mechanism of structural transitions prior to fibril formation in AL amyloidosis, which offers, in the long run, opportunities for therapeutic intervention. AL amyloidosis is caused by the accumulation of overproduced light chain (LC) fragments as fibrils in patient organs and it is the most prevalent systemic amyloidosis. Here, the authors combine biochemical and biophysical experiments to characterise the lag phase of a patient-derived truncated LC and they identify structural transitions that precede fibril formation

Multimeric ACE2-IgM fusions as broadly active antivirals that potently neutralize SARS-CoV-2 variants.

Coronavirus infections are a world-wide threat to human health. A promising strategy to develop a broadly active antiviral is the use of fusion proteins consisting of an antibody IgG Fc region and a human ACE2 domain to which the viral spike proteins bind. Here we create antiviral fusion proteins based on IgM scaffolds. The hexameric ACE2-IgM-Fc fusions can be efficiently produced in mammalian cells and they neutralize the infectious virus with picomolar affinity thus surpassing monomeric ACE2-IgM-Fc by up to 96-fold in potency. In addition, the ACE2-IgM fusion shows increased neutralization efficiency for the highly infectious SARS-CoV-2 omicron variant in comparison to prototypic SARS-CoV-2. Taken together, these multimeric IgM fusions proteins are a powerful weapon to fight coronavirus infections

Microwave alkylation of lithium tetrazolate

N1-substituted tetrazoles are interesting ligands in transition metal coordination chemistry, especially in the field of spin crossover. Their synthesis is performed in most cases according to the Franke-synthesis, using a primary amine as reagent introducing the substitution pattern. To enhance flexibility in means of substrate scope, we developed a new protocol based on alkylation of lithium tetrazolate with alkyl bromides. The N1–N2 isomerism of the tetrazole during the alkylation was successfully suppressed by use of highly pure lithium tetrazolate and 30 vol.% aqueous ethanol as solvent, leading to pure N1-substituted products. The feasibility of this reaction was demonstrated by a selection of different substrates.Austrian Science Fund (FWF