Macrocyclic peptides derived from AcPHF6* and AcPHF6 to selectively modulate the Tau aggregation.

Ten macrocyclic peptides, each comprising 14 amino acids, were designed and synthesized based on the Tau aggregation model hexapeptides AcPHF6* and AcPHF6. The design took into account the aggregation tendencies of each residue in AcPHF6* and AcPHF6, their aggregation models, while employing peptide-based structural design principles including N-methylation to promote turns and to block hydrogen bond propagation and elongation of the aggregation chain. NMR analysis supported that all these peptides adopted an antiparallel β-sheet conformation.

Total synthesis, structure elucidation and expanded bioactivity of icosalide A: effect of lipophilicity and ester to amide substitution on its bioactivity.

The first total synthesis of icosalide A, an antibacterial depsipeptide that is unique in that it contains two lipophilic beta-hydroxy acids, has been achieved by following Fmoc solid-phase peptide synthesis in combination with solution-phase synthesis. The ambiguity in the absolute stereochemistry of icosalide A has been resolved by synthesizing the reported structures and other relevant diastereomers of icosalides and comparing their NMR data. NMR-based structure elucidation of icosalide A revealed a well-folded structure with cross-strand hydrogen bonds similar to the anti-parallel beta-sheet conformation in peptides and displayed a synergistic juxtaposition of the aliphatic sidechains.

Exploration of N-Arylation of Backbone Amides as a Novel Tool for Conformational Modification in Peptides.

A set of 15 cyclic-hexaalanine and 10 cyclic-pentaalanine peptides containing one or two backbone N-aryl amide bonds were synthesized by following a combination of solution-phase and solid-phase peptide synthesis. NMR-based conformation studies of these N-aryl cyclic-hexaalanine peptides revealed five distinct template conformations with an antiparallel β-sheet structure; for N-aryl cyclic-pentaalanine peptides three template structures were revealed. All the template structures have distinct peptide-turn features.

Correction: Residue-based propensity of aggregation in the Tau amyloidogenic hexapeptides AcPHF6* and AcPHF6.

[This corrects the article DOI: 10.1039/D0RA03809A.].

HDAC6 ZnF UBP as the Modifier of Tau Structure and Function.

Histone deacetylase 6 is a class II histone deacetylase primarily present in the cytoplasm and involved in the regulation of various cellular functions. It consists of two catalytic deacetylase domains and a unique zinc finger ubiquitin binding protein domain, which sets it apart from other HDACs. HDAC6 is known to regulate cellular activities by modifying the function of microtubules, HSP90, and cortactin through deacetylation.

EGCG impedes human Tau aggregation and interacts with Tau.

Tau aggregation and accumulation is a key event in the pathogenesis of Alzheimer's disease. Inhibition of Tau aggregation is therefore a potential therapeutic strategy to ameliorate the disease. Phytochemicals are being highlighted as potential aggregation inhibitors.

Residue-based propensity of aggregation in the Tau amyloidogenic hexapeptides AcPHF6* and AcPHF6.

In Alzheimer's disease and related tauopathies, the aggregation of microtubule-associated protein, Tau, into fibrils occurs the interaction of two hexapeptide motifs PHF* VQIINK and PHF VQIVYK as β-sheets. To understand the role of the constituent amino acids of PHF and PHF* in the aggregation, a set of 12 alanine mutant peptides was synthesized by replacing each amino acid in PHF and PHF* with alanine and they were characterized by nuclear magnetic resonance (NMR) spectroscopy, circular dichroism (CD), transmission electron microscopy (TEM) and ThS/ANS fluorescence assay. Our studies show that while the aggregation was suppressed in most of the alanine mutant peptides, replacement of glutamine by alanine in both PHF and PHF* enhanced the fibrillization.

Novel cilengitide-based cyclic RGD peptides as αvβ integrin inhibitors.

In this letter, we report a series of five new RGD-containing cyclic peptides as potent inhibitors to αvβ integrin protein. We have incorporated various unnatural lipophilic amino acids into the cyclic RGD framework of cilengitide, which is selective for αvβ integrin. All the newly synthesized cyclic peptides were evaluated in vitrosolid phase binding assay and investigated for their bindingbehaviourtowards integrin subtypes.

Melatonin interacts with repeat domain of Tau to mediate disaggregation of paired helical filaments.

Tau is the major neuronal protein involved in the stabilization of microtubule assembly. In Alzheimer's disease, Tau self-assembles to form intracellular protein aggregates which are toxic to cells. Various methods have been tried and tested to restrain the aggregation of Tau.

From a Helix to a Small Cycle: Metadynamics-Inspired αvβ6 Integrin Selective Ligands.

The RGD-recognizing αvβ6 integrin has only recently emerged as a major target for cancer diagnosis and therapy. Thus, the development of selective, low-molecular-weight ligands of this receptor is still in great demand. Here, a metadynamics-driven design strategy allowed us to successfully convert a helical nonapeptide into a cyclic pentapeptide (6) showing remarkable potency and αvβ6 specificity.