Enantiomeric forms of BTD-2, PG-1, and PM-1 were synthesized to delineate the structure and function of these β-sheet antimicrobial peptides. Activity and lipid-binding assays confirm that these peptides act via a receptor-independent mechanism involving membrane interaction. The racemic crystal structure of BTD-2 solved at 1.45 Å revealed a novel oligomeric form of β-sheet antimicrobial peptides within the unit cell: an antiparallel trimer, which we suggest might be related to its membrane-active form. The BTD-2 oligomer extends into a larger supramolecular state that spans the crystal lattice, featuring a steric-zipper motif that is common in structures of amyloid-forming peptides. The supramolecular structure of BTD-2 thus represents a new mode of fibril-like assembly not previously observed for antimicrobial peptides, providing structural evidence linking antimicrobial and amyloid peptides.

Disulfide-rich macrocyclic peptides are emerging as versatile scaffolds for the development of stable biochemical tools. This potential is due to the combination of their structural stability and range of bioactivities. Here, we explored the activity of these peptides on fibril growth of the hexapeptide Ac-VQIVYK-NH2 (AcPHF6), which is a tau-derived peptide that has been widely used to understand the pathological mechanism of numerous tauopathies, including Alzheimer's disease. Of the cyclic peptides tested, SFTI-1 and kB1 showed an inherent ability to inhibit AcPHF6 fibril formation. Using an end-capping strategy and combining it with a molecular grafting approach, we demonstrated that SFTI-1 could be used as a starting point to design more potent fibril inhibitors. We further identified chemical and structural features of SFTI-1 and its analogues that underpin their inhibitory activity. The ability to inhibit fibril growth using the strategy employed herein supports the 'steric zipper' model of AcPHF6 fibril formation and shows that naturally-occurring cyclic peptides have potential as drug leads or molecular probes for understanding fibril formation.

ObjectiveTo identify the clinical phenotypes and infectious triggers in the 2019 Peruvian Guillain-Barré syndrome (GBS) outbreak.MethodsWe prospectively collected clinical and neurophysiologic data of patients with GBS admitted to a tertiary hospital in Lima, Peru, between May and August 2019. Molecular, immunologic, and microbiological methods were used to identify causative infectious agents. Sera from 41 controls were compared with cases for antibodies to Campylobacter jejuni and gangliosides. Genomic analysis was performed on 4 C jejuni isolates.ResultsThe 49 included patients had a median age of 44 years (interquartile range [IQR] 30–54 years), and 28 (57%) were male. Thirty-two (65%) had symptoms of a preceding infection: 24 (49%) diarrhea and 13 (27%) upper respiratory tract infection. The median time between infectious to neurologic symptoms was 3 days (IQR 2–9 days). Eighty percent had a pure motor form of GBS, 21 (43%) had the axonal electrophysiologic subtype, and 18% the demyelinating subtype. Evidence of recent C jejuni infection was found in 28/43 (65%). No evidence of recent arbovirus infection was found. Twenty-three cases vs 11 controls (OR 3.3, confidence interval [CI] 95% 1.2–9.2, p < 0.01) had IgM and/or IgA antibodies against C jejuni. Anti-GM1:phosphatidylserine and/or anti-GT1a:GM1 heteromeric complex antibodies were strongly positive in cases (92.9% sensitivity and 68.3% specificity). Genomic analysis showed that the C jejuni strains were closely related and had the Asn51 polymorphism at cstII gene.ConclusionsOur study indicates that the 2019 Peruvian GBS outbreak was associated with C jejuni infection and that the C jejuni strains linked to GBS circulate widely in different parts of the world.