We explore the chemical space of Pseudomonas quinolone signal analogs as privileged structures and report the discovery of a thioquinolone as a potent inhibitor of the important virulence factor elastase of the human pathogen Pseudomonas aeruginosa. We provide evidence that the derivative binds to the active site zinc of elastase and additionally acts as a fluorescent zinc sensor.

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Aluminium (Al) is clearly neurotoxic and considerable evidence exists that Al may play a role in the aetiology or pathogenesis of Alzheimer’s disease (AD). Nevertheless, the link between AD pathology and Al is still open to debate. Therefore, we investigated here the interaction of aluminium ions with two Aβ peptide fragments and their analogues. First, we synthesised by the Fmoc/tBu solid-phase peptide synthesis (SPPS) strategy using an automated peptide synthesiser two new peptides starting from the Aβ(1–16) native peptide fragment. For this purpose, the three histidine residues (H6, H13, and H14) of the Aβ(1–16) peptide were replaced by three alanine and three serine residues to form the modified peptides Aβ(1–16)A36,13,14 and Aβ(1–16)S36,13,14 (primary structures: H-1DAEFRADSGYEVAAQK16-NH2 and H-1DAEFRSDSGYEVSSQK16-NH2). In addition, the Aβ(9–16) peptide fragment (H-9GYEVHHQK16-NH2) and its glycine analogues, namely Aβ(9–16)G110, (H-9GGEVHHQK16-NH2), Aβ(9–16)G213,14 (H-9GYEVGGQK16-NH2), and Aβ(9–16)G310,13,14 (H-9GGEVGGQK16-NH2), were manually synthesised in order to study Al binding to more specific amino acid residues. Both the peptides and the corresponding complexes with aluminium were comparatively investigated by mass spectrometry (MS), circular dichroism spectroscopy (CD), atomic force microscopy (AFM), scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FT-IR). Al–peptide molecular ions and Al-fragment ions were unambiguously identified in the MS and MS/MS spectra. AFM images showed dramatic changes in the film morphology of peptides upon Al binding. Our findings from the investigation of N-terminal 1-16 and even 9-16 normal and modified sequences of Aβ peptides suggest that they have the capability to be involved in aluminium ion binding associated with AD.

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Alzheimer's disease (AD) is the most common cause of dementia and one of its major neuropathological features is the extracellular deposition of fibrils composed of amyloid-β peptides (Aβ). Our investigation started with a small fragment of Aβ, namely the amyloid Aβ (9-16) peptide (9 GYEVHHQK 16). Here, we report on the synthesis of four new peptides obtained by replacing with glycine or phenylalanine some amino acid residues in the sequence of the above-mentioned Aβ (9-16) peptide, in order to use them to study the oligomerization and fibrillation processes in the presence of metal ions. The following peptides were synthesized by Fmoc/t-butyl solid-phase synthesis (SPPS) strategy: Aβ (9-16) (9 GYEVHHQK 16), Aβ (9-16) G (9 G 10 GEVHHQK 16), Aβ (9-16) F (9 G 10 FEVHHQK 16), Aβ (9-16) GG (9 G 10 YEV 13 G 14 GQK 16) and Aβ (9-16) GGG (9 G 10 GEV 13 G 14 GQK 16). The newly synthesized peptides were purified by RP-HPLC and characterized by MALDI-TOF mass spectrometry and Fourier transform infrared spectroscopy (FT-IR) as well as, theoretically, using the GPMAW software. Mass spectrometric spectra confirmed the successful synthesis of the desired peptides, while the hydrophobicity parameter, simulated with the GPMAW software, was shown to be dependent on the structure of each peptide. Infrared spectroscopy showed that the conformation of peptides differs from a peptide to another. Such analogs of Aβ (9-16) peptide fragment are supposed to be of interest in searching the role played by certain amino acids in AD aetiology and, in general, in neurodegeneration.

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