Quinolinic Acid Amyloid-like Fibrillar Assemblies Seed α-Synuclein Aggregation

Quinolinic acid (QA), a downstream neurometabolite in the kynurenine pathway, the biosynthetic pathway of tryptophan, is associated with neurodegenerative diseases pathology. Mutations in genes encoding kynurenine pathway enzymes, which control the level of QA production, are linked with elevated risk of developing Parkinson\u27s disease. Recent findings have revealed the accumulation and deposition of QA in post-mortem samples, as well as in cellular models of Alzheimer\u27s disease and related disorders. Furthermore, intrastriatal inoculation of mice with QA results in increased levels of phosphorylated α-synuclein and neurodegenerative pathological and behavioral characteristics. However, the cellular and molecular mechanisms underlying the involvement of QA accumulation in protein aggregation and neurodegeneration remain elusive. We recently established that self-assembled ordered structures are formed by various metabolites and hypothesized that these “metabolite amyloids” may seed amyloidogenic proteins. Here we demonstrate the formation of QA amyloid-like fibrillar assemblies and seeding of α-synuclein aggregation by these nanostructures both in vitro and in cell culture. Notably, α-synuclein aggregation kinetics was accelerated by an order of magnitude. Additional amyloid-like properties of QA assemblies were demonstrated using thioflavin T assay, powder X-ray diffraction and cell apoptosis analysis. Moreover, fluorescently labeled QA assemblies were internalized by neuronal cells and co-localized with α-synuclein aggregates. In addition, we observed cell-to-cell propagation of fluorescently labeled QA assemblies in a co-culture of treated and untreated cells. Our findings suggest that excess QA levels, due to mutations in the kynurenine pathway, for example, may lead to the formation of metabolite assemblies that seed α-synuclein aggregation, resulting in neuronal toxicity and induction of Parkinson\u27s disease

Metal-driven folding and assembly of a minimal β-sheet into a 3D-porous honeycomb framework

This research was supported by the DST Inspire Faculty Fellowship (No. DST/INSPIRE/04/2020/002499), and National Institute of Pharmaceutical Education and Research, S. A. S. Nagar. S. B. thanks SERB, Govt. of India for the Ramanujan Fellowship (ref. no. RJF/2022/000042) and Ashoka University.In contrast to short helical peptides, constrained peptides, and foldamers, the design and fabrication of crystalline 3D frameworks from the β-sheet peptides are rare because of their high self-aggregation propensity to form 1D architectures. Herein, we demonstrate the formation of a 3D porous honeycomb framework through the silver coordination of a minimal β-sheet forming a peptide having terminal metal coordinated 4- and 3-pyridyl ligands.Peer reviewe

Peptide hydrogen-bonded organic frameworks

This research was supported by the DST Inspire Faculty Fellowship (No. DST/INSPIRE/04/2020/002499) from the Department of Science and Technology, New Delhi. R. M. is also thankful to the National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, for providing the research facilities. T. V. thanks Tel Aviv University for the postdoctoral fellowship. E. G. thanks European Research Council PoC project PepZoPower (101101071). A. I. N. thanks the American Chemical Society Petroleum Research Fund (62285-DNI). S. B. thanks SERB, Govt. of India, for the Ramanujan Fellowship (Ref. no. RJF/2022/000042), and Ashoka University, Sonipat, Haryana, for the infrastructure. S. N. acknowledges Vellore Institute of Technology Chennai for the funding and infrastructure.Hydrogen-bonded porous frameworks (HPFs) are versatile porous crystalline frameworks with diverse applications. However, designing chiral assemblies or biocompatible materials poses significant challenges. Peptide-based hydrogen-bonded porous frameworks (P-HPFs) are an exciting alternative to conventional HPFs due to their intrinsic chirality, tunability, biocompatibility, and structural diversity. Flexible, ultra-short peptide-based P-HPFs (composed of 3 or fewer amino acids) exhibit adaptable porous topologies that can accommodate a variety of guest molecules and capture hazardous greenhouse gases. Longer, folded peptides present challenges and opportunities in designing P-HPFs. This review highlights recent developments in P-HPFs using ultra-short peptides, folded peptides, and foldamers, showcasing their utility for gas storage, chiral recognition, chiral separation, and medical applications. It also addresses design challenges and future directions in the field.Peer reviewe

Terminal Peptide Directed Assembly of Naphthalene-Bisimides

The self-assembly of two naphthalene-bisimide based nonionic bolaamphiphiles containing two terminal tripeptide moieties has been investigated. The bisimide <b>1</b> containing a core of adjacent aromatic rings and two termini of folded tripeptide moieties (-Tyr-Aib-Leu-OMe) adopts a dumbbell shape conformation, and it self-assembles through noncovalent interactions to fabricate microspheres. In contrast, the bisimide <b>2</b> containing two termini of extended tripeptide moieties (-Phe-Phe-Tyr-OMe) adopts a wrist band shape structure, and it self-assembles to produce elongated fibrils. The X-ray crystallography reveals that the bisimide <b>1</b> adopts a dumbbell shape with two terminal β-turns, and it self-associates to form a rhombus-like structure in higher order packing. Moreover, the conductivity of the bisimide <b>2</b> is 2 orders of magnitude higher than that of the bisimide <b>1</b> in room light. The secondary structures of the terminal tripeptides of bisimide systems and the peptide–peptide interactions are the driving forces for the assembly process

Inhibition of Fibril Formation by Tyrosine Modification of Diphenylalanine: Crystallographic Insights

The self-assemblies of diphenylalanine and its tyrosine analogues have been investigated. The peptide Boc-Phe-Phe-OMe (<b>1</b>), having a sequence identity with the central hydrophobic cluster (CHC) of Alzheimer’s β-amyloid diphenylalanine motif, self-assembles to produce twisted fibrils. In contrast, the tyrosine-modified analogues Boc-Phe-Tyr-OMe (<b>2</b>), Boc-Tyr-Phe-OMe (<b>3</b>), and Boc-Tyr-Tyr-OMe (<b>4</b>), self-assemble to form microspheres. The X-ray crystallography reveal that the peptide <b>1</b> adopts an inverse γ-turn structure and self-associates as a hydrogen-bonded chain of molecules along a 2-fold screw axis, whereas the tyrosine-modified analogues exhibit parallel β-sheet aggregation and cyclic packing in higher-order assembly. The structural analysis of the peptides as described here can serve as a basis for de novo design and therapeutics

Inhibition of Fibril Formation by Tyrosine Modification of Diphenylalanine: Crystallographic Insights

The self-assemblies of diphenylalanine and its tyrosine analogues have been investigated. The peptide Boc-Phe-Phe-OMe (<b>1</b>), having a sequence identity with the central hydrophobic cluster (CHC) of Alzheimer’s β-amyloid diphenylalanine motif, self-assembles to produce twisted fibrils. In contrast, the tyrosine-modified analogues Boc-Phe-Tyr-OMe (<b>2</b>), Boc-Tyr-Phe-OMe (<b>3</b>), and Boc-Tyr-Tyr-OMe (<b>4</b>), self-assemble to form microspheres. The X-ray crystallography reveal that the peptide <b>1</b> adopts an inverse γ-turn structure and self-associates as a hydrogen-bonded chain of molecules along a 2-fold screw axis, whereas the tyrosine-modified analogues exhibit parallel β-sheet aggregation and cyclic packing in higher-order assembly. The structural analysis of the peptides as described here can serve as a basis for de novo design and therapeutics

Disordered Protein Stabilization by Co-Assembly of Short Peptides Enables Formation of Robust Membranes

Molecular self-assembly is a spontaneous natural process resulting in highly ordered nano to microarchitectures. We report temperature-independent formation of robust stable membranes obtained by the spontaneous interaction of intrinsically disordered elastin-like polypeptides (ELPs) with short aromatic peptides at temperatures both below and above the conformational transition temperature of the ELPs. The membranes are stable over time and display durability over a wide range of parameters including temperature, pH, and ultrasound energy. The morphology and composition of the membranes were analyzed using microscopy. These robust structures support preosteoblast cell adhesion and proliferation as well as pH-dependent cargo release. Simple noncovalent interactions with short aromatic peptides can overcome conformational restrictions due to the phase transition to facilitate the formation of complex bioactive scaffolds that are stable over a wide range of environmental parameters. This approach offers novel possibilities for controlling the conformational restriction of intrinsically disordered proteins and using them in the design of new materials

Porous Organic Material from Discotic Tricarboxyamide: Side Chain–Core interactions

The benzene-1,3,5-tricarboxyamide containing three l-methionine (<b>1</b>) self-assemble through 3-fold amide–amide hydrogen bonds and π–π stacking to fabricate one-dimensional nanorod like structure. However, the tyrosine analogue (<b>2</b>) carrying multiple H-bonding side chains lost the <i>C</i>₃ symmetry and 3-fold amide–amide hydrogen bonds and developed a porous structure. The porous material exhibits ten times more N₂ sorption (155 cc/g) than the columnar one, indicating that side chain–core interactions have a drastic effect on structure and function