Structural and Conformational Dynamics of Self-Assembling Bioactive β‑Sheet Peptide Nanostructures Decorated with Multivalent RNA-Binding Peptides

Understanding the dynamic behavior of nanostructural systems is important during the development of controllable and tailor-made nanomaterials. This is particularly true for nanostructures that are intended for biological applications because biomolecules are usually highly dynamic and responsive to external stimuli. In this Article, we investigated the structural and conformational dynamics of self-assembling bioactive β-sheet peptide nanostructures using electron paramagnetic resonance (EPR) spectroscopy. The model peptide nanostructures are characterized by the cross-β spine of β-ribbon fibers and multiple RNA-binding bioactive peptides that constitute the shell of the nanostructures. We found first, that bioactive peptides at the shell of β-ribbon nanostructure have a mobility similar to that of an isolated monomeric peptide. Second, the periphery of the cross-β spine is more immobile than the distal part of surface-displayed bioactive peptides. Third, the rotational dynamics of short and long fibrils are similar; that is, the mobility is largely independent of the extent of aggregation. Fourth, peptides that constitute the shell are affected first by the external environment at the initial stage. The cross-β spine resists its external environment to a certain extent and abruptly disintegrates when the perturbation reaches a certain degree. Our results provide an overall picture of β-sheet peptide nanostructure dynamics, which should be useful in the development of dynamic self-assembled peptide nanostructures

Selective Electrocatalytic Reduction of Nitrite to Dinitrogen Based on Decoupled Proton–Electron Transfer

The development of denitrification catalysts which can reduce nitrate and nitrite to dinitrogen is critical for sustaining the nitrogen cycle. However, regulating the selectivity has proven to be a challenge, due to the difficulty of controlling complex multielectron/proton reactions. Here we report that utilizing sequential proton–electron transfer (SPET) pathways is a viable strategy to enhance the selectivity of electrochemical reactions. The selectivity of an oxo-molybdenum sulfide electrocatalyst toward nitrite reduction to dinitrogen exhibited a volcano-type pH dependence with a maximum at pH 5. The pH-dependent formation of the intermediate species (distorted Mo­(V) oxo species) identified using operando electron paramagnetic resonance (EPR) and Raman spectroscopy was in accord with a mathematical prediction that the p<i>K</i>_a of the reaction intermediates determines the pH-dependence of the SPET-derived product. By utilizing this acute pH dependence, we achieved a Faradaic efficiency of 13.5% for nitrite reduction to dinitrogen, which is the highest value reported to date under neutral conditions

Mechanistic Insights into Tunable Metal-Mediated Hydrolysis of Amyloid‑β Peptides

An amyloidogenic peptide, amyloid-β (Aβ), has been implicated as a contributor to the neurotoxicity of Alzheimer’s disease (AD) that continues to present a major socioeconomic burden for our society. Recently, the use of metal complexes capable of cleaving peptides has arisen as an efficient tactic for amyloid management; unfortunately, little has been reported to pursue this strategy. Herein, we report a novel approach to validate the hydrolytic cleavage of divalent metal complexes toward two major isoforms of Aβ (Aβ₄₀ and Aβ₄₂) and tune their proteolytic activity based on the choice of metal centers (M = Co, Ni, Cu, and Zn) which could be correlated to their anti-amyloidogenic properties. Such metal-dependent tunability was facilitated employing a tetra-<i>N</i>-methylated cyclam (TMC) ligand that imparts unique geometric and stereochemical control, which has not been available in previous systems. Co­(II)­(TMC) was identified to noticeably cleave Aβ peptides and control their aggregation, reporting the first Co­(II) complex for such reactivities to the best of our knowledge. Through detailed mechanistic investigations by biochemical, spectroscopic, mass spectrometric, and computational studies, the critical importance of the coordination environment and acidity of the aqua-bound complexes in promoting amide hydrolysis was verified. The biological applicability of Co­(II)­(TMC) was also illustrated via its potential blood-brain barrier permeability, relatively low cytotoxicity, regulatory capability against toxicity induced by both Aβ₄₀ and Aβ₄₂ in living cells, proteolytic activity with Aβ peptides under biologically relevant conditions, and inertness toward cleavage of structured proteins. Overall, our approaches and findings on reactivities of divalent metal complexes toward Aβ, along with the mechanistic insights, demonstrate the feasibility of utilizing such metal complexes for amyloid control

Phosphonate Pendant Armed Propylene Cross-Bridged Cyclam: Synthesis and Evaluation as a Chelator for Cu-64

A propylene cross-bridged macrocyclic chelator with two phosphonate pendant arms (PCB-TE2P) was synthesized from cyclam. Various properties of the synthesized chelator, including Cu-complexation, Cu-complex stability, ⁶⁴Cu-radiolabeling, and in vivo behavior, were studied and compared with those of a previously reported propylene cross-bridged chelator (PCB-TE2A)

Mechanistic Investigation of Water Oxidation Catalyzed by Uniform, Assembled MnO Nanoparticles

The development of active water oxidation catalysts is critical to achieve high efficiency in overall water splitting. Recently, sub-10 nm-sized monodispersed partially oxidized manganese oxide nanoparticles were shown to exhibit not only superior catalytic performance for oxygen evolution, but also unique electrokinetics, as compared to their bulk counterparts. In the present work, the water-oxidizing mechanism of partially oxidized MnO nanoparticles was investigated using integrated in situ spectroscopic and electrokinetic analyses. We successfully demonstrated that, in contrast to previously reported manganese (Mn)-based catalysts, Mn­(III) species are stably generated on the surface of MnO nanoparticles via a proton-coupled electron transfer pathway. Furthermore, we confirmed as to MnO nanoparticles that the one-electron oxidation step from Mn­(II) to Mn­(III) is no longer the rate-determining step for water oxidation and that Mn­(IV)O species are generated as reaction intermediates during catalysis

Hydrated Manganese(II) Phosphate (Mn₃(PO₄)₂·3H₂O) as a Water Oxidation Catalyst

The development of a water oxidation catalyst has been a demanding challenge in realizing water splitting systems. The asymmetric geometry and flexible ligation of the biological Mn₄CaO₅ cluster are important properties for the function of photosystem II, and these properties can be applied to the design of new inorganic water oxidation catalysts. We identified a new crystal structure, Mn₃(PO₄)₂·3H₂O, that precipitates spontaneously in aqueous solution at room temperature and demonstrated its high catalytic performance under neutral conditions. The bulky phosphate polyhedron induces a less-ordered Mn geometry in Mn₃(PO₄)₂·3H₂O. Computational analysis indicated that the structural flexibility in Mn₃(PO₄)₂·3H₂O could stabilize the Jahn–Teller-distorted Mn­(III) and thus facilitate Mn­(II) oxidation. This study provides valuable insights into the interplay between atomic structure and catalytic activity

(7‑Benzyloxy-2,3-dihydro-<i>1H</i>-pyrrolo[1,2‑<i>a</i>]indol-1-yl)acetic Acids as S1P₁ Functional Antagonists

S1P₁ is a validated target for treatment of autoimmune disease, and functional antagonists with superior safety and pharmacokinetic properties are being sought as second generation therapeutics. We describe the discovery and optimization of (7-benzyloxy-2,3-dihydro-<i>1H</i>-pyrrolo­[1,2-<i>a</i>]­indol-1-yl)­acetic acids as potent, centrally available, direct acting S1P₁ functional antagonists, with favorable pharmacokinetic and safety properties

Discovery of APD334: Design of a Clinical Stage Functional Antagonist of the Sphingosine-1-phosphate‑1 Receptor

APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P₁ receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P₁ and has a favorable PK/PD profile, producing robust lymphocyte lowering at relatively low plasma concentrations in several preclinical species. This new agent was efficacious in a mouse experimental autoimmune encephalomyelitis (EAE) model of MS and a rat collagen induced arthritis (CIA) model and was found to have appreciable central exposure