Mitochondria-Penetrating Peptides

SummaryMitochondria are important targets for cancer chemotherapy and other disease treatments. Gaining access to this organelle can be difficult, as the inner membrane is a barrier limiting diffusive transport. A mitochondrial molecular carrier would be a boon to the development of organelle-specific therapeutics. Here, we report a significant advance in the development of mitochondrial transporters—synthetic cell-permeable peptides that are able to enter mitochondria. Efficient uptake of these mitochondria-penetrating peptides (MPPs) is observed in a variety of cell types, and organellar specificity is attained with sequences that possess specific chemical properties. The MPPs identified are cationic, but also lipophilic; this combination of characteristics facilitates permeation of the hydrophobic mitochondrial membrane. The examination of a panel of MPPs illustrates that mitochondrial localization can be rationally controlled and finely tuned by altering lipophilicity and charge

Advancing the speed, sensitivity and accuracy of biomolecular detection using multi-length-scale engineering

Rapid progress in identifying disease biomarkers has increased the importance of creating high-performance detection technologies. Over the last decade, the design of many detection platforms has focused on either the nano or micro length scale. Here, we review recent strategies that combine nano- and microscale materials and devices to produce large improvements in detection sensitivity, speed and accuracy, allowing previously undetectable biomarkers to be identified in clinical samples. Microsensors that incorporate nanoscale features can now rapidly detect disease-related nucleic acids expressed in patient samples. New microdevices that separate large clinical samples into nanocompartments allow precise quantitation of analytes, and microfluidic systems that utilize nanoscale binding events can detect rare cancer cells in the bloodstream more accurately than before. These advances will lead to faster and more reliable clinical diagnostic devices

Intercalative Stacking: A Critical Feature of DNA Charge-Transport Electrochemistry

In electrochemistry experiments on DNA-modified electrodes, features of the redox probe that determine efficient charge transport through DNA-modified surfaces have been explored using methylene blue (MB^+) and Ru(NH_3)_6^(3+) as DNA-binding redox probes. The electrochemistry of these molecules is studied as a function of ionic strength to determine the necessity of tight binding to DNA and the number of electrons involved in the redox reaction; on the DNA surface, MB^+ displays 2e^-/1H^+ electrochemistry (pH 7) and Ru(NH^3)_6^(3+) displays 1e^- electrochemistry. We examine also the effect of electrode surface passivation and the effect of the mode (intercalation or electrostatic) of MB^+ and Ru(NH_3)_6^(3+) binding to DNA to highlight the importance of intercalation for reduction by a DNA-mediated charge-transport pathway. Furthermore, in experiments in which MB^+ is covalently linked to the DNA through a σ-bonded tether and the ionic strength is varied, it is demonstrated that intercalative stacking rather than covalent σ-bonding is essential for efficient reduction of MB^+. The results presented here therefore establish that efficient charge transport to the DNA-binding moiety in DNA films requires intercalative stacking and is mediated by the DNA base pair array

Synthesis and Spectroelectrochemistry of Ir(bpy)(phen)(phi)^(3+), a Tris(heteroleptic) Metallointercalator

A tris(heteroleptic) phenanthrenequinone diimine (phi) complex of Ir(III), Ir(bpy)(phen)(phi)^(3+), was synthesized through the stepwise introduction of three different bidentate ligands, and the Λ- and Δ-enantiomers were resolved and characterized by CD spectroscopy. Like other phi complexes, this tris(heteroleptic) iridium complex binds avidly to DNA by intercalation. Electrochemical studies show that Ir(bpy)(phen)(phi)^(3+) undergoes a reversible one-electron reduction at E_0 = -0.025 V in 0.1 M TBAH/DMF (versus Ag/AgCl), and spectroelectrochemical studies indicate that this reduction is centered on the phi ligand. The EPR spectrum of electrochemically generated Ir(bpy)(phen)(phi)^(2+) is consistent with a phi-based radical. The electrochemistry of Ir(bpy)(phen)(phi)^(3+) was also probed at a DNA-modified electrode, where a DNA binding affinity of K = 1.1 x 10^6 M^(-1) was measured. In contrast to Ir(bpy)(phen)(phi)^(3+) free in solution, the complex bound to DNA undergoes a concerted two-electron reduction, to form a diradical species. On the basis of UV-visible and EPR spectroscopies, it is found that disproportionation of electrochemically generated Ir(bpy)(phen) (phi)^(2+) occurs upon DNA binding. These results underscore the rich redox chemistry associated with metallointercalators bound to DNA

Multi-cation perovskites prevent carrier reflection from grain surfaces

© 2020, The Author(s), under exclusive licence to Springer Nature Limited. The composition of perovskite has been optimized combinatorially such that it often contains six components (AxByC1−x−yPbXzY3−z) in state-of-art perovskite solar cells. Questions remain regarding the precise role of each component, and the lack of a mechanistic explanation limits the practical exploration of the large and growing chemical space. Here, aided by transient photoluminescence microscopy, we find that, in perovskite single crystals, carrier diffusivity is in fact independent of composition. In polycrystalline thin films, the different compositions play a crucial role in carrier diffusion. We report that methylammonium (MA)-based films show a high carrier diffusivity of 0.047 cm2 s−1, while MA-free mixed caesium-formamidinium (CsFA) films exhibit an order of magnitude lower diffusivity. Elemental composition studies show that CsFA grains display a graded composition. This curtails electron diffusion in these films, as seen in both vertical carrier transport and surface potential studies. Incorporation of MA leads to a uniform grain core-to-edge composition, giving rise to a diffusivity of 0.034 cm2 s−1 in CsMAFA films. A model that invokes competing crystallization processes allows us to account for this finding, and suggests further strategies to achieve homogeneous crystallization for the benefit of perovskite optoelectronics

Electron transfer through the DNA double helix: spectroscopic and electrochemical studies

NOTE: Text or symbols not renderable in plain ASCII are indicated by [...]. Abstract is included in .pdf document. The DNA helix, containing a stacked array of aromatic base pairs, presents a novel medium in which electron transfer mediated by a molecular [pi]-stack can be investigated. To probe electron transfer through DNA, we have constructed duplex assemblies modified with photo- and redox-active probes and applied spectroscopic and electrochemical approaches to the study of DNA-mediated charge transport. Photoinduced electron transfer between intercalators was examined as a function of distance in a series of small DNA duplexes covalently modified with ethidium (Et) and [...]. At distances up to 35 [...], electron transfer occurs on the subnanosecond time scale ([...]). In duplexes containing disruptive base mismatches, large decreases in electron-transfer yields are observed, confirming that the electron transfer pathway proceeds through the stacked base pairs. Hence, it was demonstrated for the first time that DNA-mediated electron transfer between intercalators is exceptionally efficient, only weakly dependent on distance, but highly sensitive to perturbations in base stacking. To investigate a DNA base within the [pi]-stack as a reactant, ethidium-modified duplexes containing the base analogue deazaguanine were synthesized. The photooxidation of deazaguanine by ethidium also proceeds on a subnanosecond time scale ([...]) and exhibits a shallow distance dependence. The efficiency and overall distance dependence is sensitive to the stacking of deazaguanine as determined by flanking sequence. These studies again showed that the DNA base stack can mediate extremely fast, long-range charge transport, and further elucidated that stacking interactions are critical in modulating the efficiency of this phenomenon. Using base-base photochemistry, electron transfer through DNA was probed directly without external donors and acceptors. Using fluorescent analogues of adenine that selectively oxidize guanine, electron transfer through the DNA [pi]-stack was investigated as a function of reactant stacking and energetics. Small variations in each of these factors lead to remarkable changes in the kinetics of DNA-mediated electron transfer and values of [beta], a parameter reflecting the exponential dependence of electron transfer on distance, were measured ranging from [...] to [...]. The DNA base stack was shown to exhibit insulator to "wire"-like properties, depending on the structure and energetics of reactants employed to probe this medium. To investigate DNA-mediated electron transfer using electrochemical methods, we assembled DNA films and incorporated intercalating redox-active molecules into the monolayers. Surface characterization techniques were employed to determine the orientation of the DNA helices within the films. With the intercalator daunomycin crosslinked to DNA duplexes immobilized on gold, efficient electron transfer over distances greater than 30 [...] was observed. Base mismatches also attenuate this long-range reaction, providing a new method for the electrochemical detection of genomic mutations. These studies have provided essential measurements of electron transfer in DNA over known, fixed distances. It is now apparent that stacking interactions modulate the efficiency of this phenomenon, an observation that may explain the range of conflicting results reported within this field. Moreover, as experimental evidence increasingly supports the notion that ultrafast charge transport can occur through the DNA helix over long distances, the implications for biological systems can now be considered. Our findings point to the DNA [pi]-stack as not only a carrier of genetic information, but also a pathway which is conducive to charge transport

Electron Transfer Between Bases in Double Helical DNA

Fluorescent analogs of adenine that selectively oxidize guanine were used to investigate photoinduced electron transfer through the DNA π-stack as a function of reactant stacking and energetics. Small variations in these factors led to profound changes in the kinetics and distance dependences of DNA-mediated electron-transfer reactions. Values of β, a parameter reflecting the dependence of electron transfer on distance, ranged from 0.1 to 1.0 per angstrom. Strong stacking interactions result in the fastest electron-transfer kinetics. Electrons are thus transported preferentially through an intrastrand rather than interstrand pathway. Reactant energetics also modulate the distance dependence of DNA-mediated charge transport. These studies may resolve the range of disparate results previously reported, and paradigms must now be developed to describe these properties of the DNA π-stack, which can range from insulator- to “wire”-like