Interaction between Amyloid Beta Peptide and an Aggregation Blocker Peptide Mimicking Islet Amyloid Polypeptide

Assembly of amyloid-beta peptide (Aβ) into cytotoxic oligomeric and fibrillar aggregates is believed to be a major pathologic event in Alzheimer's disease (AD) and interfering with Aβ aggregation is an important strategy in the development of novel therapeutic approaches. Prior studies have shown that the double N-methylated analogue of islet amyloid polypeptide (IAPP) IAPP-GI, which is a conformationally constrained IAPP analogue mimicking a non-amyloidogenic IAPP conformation, is capable of blocking cytotoxic self-assembly of Aβ. Here we investigate the interaction of IAPP-GI with Aβ40 and Aβ42 using NMR spectroscopy. The most pronounced NMR chemical shift changes were observed for residues 13–20, while residues 7–9, 15–16 as well as the C-terminal half of Aβ - that is both regions of the Aβ sequence that are converted into β-strands in amyloid fibrils - were less accessible to solvent in the presence of IAPP-GI. At the same time, interaction of IAPP-GI with Aβ resulted in a concentration-dependent co-aggregation of Aβ and IAPP-GI that was enhanced for the more aggregation prone Aβ42 peptide. On the basis of the reduced toxicity of the Aβ peptide in the presence of IAPP-GI, our data are consistent with the suggestion that IAPP-GI redirects Aβ into nontoxic “off-pathway” aggregates

West-Life: A Virtual Research Environment for structural biology

The West-Life project (https://about.west-life.eu/)is a Horizon 2020 project funded by the European Commission to provide data processing and data management services for the international community of structural biologists, and in particular to support integrative experimental approaches within the field of structural biology. It has developed enhancements to existing web services for structure solution and analysis, created new pipelines to link these services into more complex higher-level workflows, and added new data management facilities. Through this work it has striven to make the benefits of European e-Infrastructures more accessible to life-science researchers in general and structural biologists in particular

Small molecule probes of protein aggregation

Understanding the mechanisms of amyloid formation and toxicity remain major challenges. Whilst substantial progress has been made in the development of methods able to identify the species formed during self-assembly and to describe the kinetic mechanisms of aggregation, the structure(s) of non-native species, including potentially toxic oligomers, remain elusive. Moreover, how fibrils contribute to disease remains unclear. Here we review recent advances in the development of small molecules and other reagents that are helping to define the mechanisms of protein aggregation in molecular detail. Such probes form a powerful platform with which to better define the mechanisms of structural conversion into amyloid fibrils and may provide the much-needed stepping stone for future development of successful therapeutic agents

Towards a muon collider

A muon collider would enable the big jump ahead in energy reach that is needed for a fruitful exploration of fundamental interactions. The challenges of producing muon collisions at high luminosity and 10 TeV centre of mass energy are being investigated by the recently-formed International Muon Collider Collaboration. This Review summarises the status and the recent advances on muon colliders design, physics and detector studies. The aim is to provide a global perspective of the field and to outline directions for future work

Ile/allo-Ile Dyad: Lack of Screw-Sense Control of the 310-Helical Structure by \u3b2-Carbon Configuration.

K. Rolka, P. Rekowski, and J. Silberring Eds., Kenes Int., Geneva, Switzerland, 2007, pp. 24-25

Handedness Control of Peptide Helices by Amino Acid Side-Chain Chirality: Ile/aIle Peptides

A set of four hexapeptide sequences, each characterized by four strongly helicogenic Aib residues and all combinations of two isomeric Ile/aIle residues at positions 2 and 5, was synthesized by solution methods and fully characterized. A detailed solution (by FT\u2013IR absorption, NMR, and CD techniques) and solid/crystalline state (by X-ray diffraction) conformational investigation allowed us to validate our assumption that all four peptides are folded in well-developed 310-helical structures. However, the most relevant conformational conclusion extracted from the present 3D-analysis is that the handedness of the 310-helical structures formed does not seem to be sensitive to the configurational change at the \u3b2-carbon atom of the constituent Ile versus the diastereomeric aIle residues (in other words, the dominant control on this important structural parameter appears to be exerted by the chirality of the amino acid \u3b1-carbon atom). These results complement published findings on the diverging relative stabilities of the intermolecularly H-bonded \u3b2-sheet structures generated by Ile versus aIle homo-oligopeptides

Guided folding takes a start from the molecular imprinting of structured epitopes

A biomimetic route towards assisted folding was explored. Molecularly imprinted polymeric nanoparticles (MIP NPs), i.e. biomimetics with entailed molecular recognition properties made by a template assisted synthesis, were prepared to target a structured epitope: the cystine containing peptide CC9ox, which corresponds to the apical portion of the \u3b2-hairpin hormone Hepcidin-25. The structural selection was achieved by the MIP NPs; moreover, the MIP NPs demonstrated favouring the folding of the linear random peptide (CC9red) into the structured one (CC9ox), anticipating the future role of the MIP NPs as in situ nanomachines to counteract folding defects

Crystal-state 3D-structural characterization of novel, Aib-based, turn and helical peptides

The crystal-state conformations of the hexapeptide amide Pht-(Aib)6-NH-C(CH3)2-O-OtBu (7), the hexapeptide Ac-L-aIle-(Aib)5-OtBu (6), the pentapeptide Z-(Aib)3-L-Glu(OtBu)-Aib-O-(CH2)2-(1)Nap (5), the tetrapeptides Z-(Aib)2-L-His(N\u3c4-Trt)-Aib-OMe (4 I) and Z-(Aib)2-L-Nva-Aib-OtBu (4 II), the tripeptide Pyr-(Aib)3-OtBu (3 I), the dipeptide amides Pyr-(Aib)2-(4)NH-TEMPO (3 II) and Piv-(Aib)2-NH-C(CH3)2-O-OtBu (3 III), and the dipeptides Pht-Aib-\u3b2Ac6c-OtBu (2 I), Pht-Aib-NH-C(CH3)2-O-OtBu (2 II) and Boc-gGly-mAib-OH (2 III) have been determined by X-ray diffraction analyses. All peptides investigated are characterized by one or more turn/helix forming Aib residues. Except the three short dipeptides, all are folded into CO\ub7\ub7\ub7HN intramolecularly H-bonded 310-helices, or into various types of \u3b2-turns. In the structure of 6, two independent molecules of opposite screw sense were observed in the asymmetric unit, generating diastereomeric 310-helice

MOLECULARLY IMPRINTED NANOPARTICLES FOR HEPCIDIN CAPTURE: A SYNTHETIC ALTERNATIVE TO NATURAL ANTIBODIES

synthesis of molecularly imprinted nanoparticles for hepcidin selective recognitio