Solvent-induced modulation of sensitivity and selectivity in the self-assembly of tetracationic cyclophanes with cholesterol sulphate, sodium dodecyl sulfate, and sodium dodecyl benzene sulfonate: Observations of significant shifts

Article

作者: Tripathi, Neetu

Cyclophane CP-1 demonstrates markedly distinct sensitivities toward Cholesterol sulfate (CH-S), Sodium Dodecyl Sulfate (SDS), and Sodium Dodecyl Benzene Sulfonate (SDBS) when the solvent is shifted minimally from a 95 % to a 98 % HEPES-DMSO mixture. In a 98:2 HEPES-DMSO mixture, CP-1 engages in highly selective self-assembly with CH-S, which is characterized by aggregation-induced emission enhancement (AIEE) in contrast to other steroidal sulfates such as pregnenolone sulfate (PRG-S), dehydroisoandrosterone sulfate (DIAND-S), taurocholic acid (TACH-S), and the surfactants SDS and SDBS. This assembly results in an approximate 40-fold increase in fluorescence intensity with three equivalents of CH-S and allows for the detection of concentrations as low as 200 nM under physiological conditions. Dynamic light scattering (DLS) studies illustrate the aggregation of CP-1 and CH-S, with the zeta potential of each shifting from negative values to nearly zero in a 1:2 CP-1:CH-S mixture, indicating self-assembly. This aggregation behavior is reversible, as demonstrated by a corresponding decrease and then increase in fluorescence intensity with temperature variations from 25 °C to 70 °C and back to 25 °C. Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) analyses show that CP-1 forms aggregates ranging from 100 to 180 nm, which increase to 150-250 nm upon interaction with CH-S. In a 95:5 HEPES-DMSO mixture, CP-1 exhibits a stronger AIEE response with SDS and SDBS compared to CH-S. Cyclophane CP-2, when dissolved in binary DMSO-water mixtures with water content exceeding 80 %, shows similar AIEE phenomena and undergoes selective fluorescence quenching with SDS and only a 50 % increase in fluorescence intensity with CH-S, irrespective of the HEPES concentration (95 % or 98 %).

2024-08-01·Small

Multifunctional Liposomes Targeting Amyloid‐β Oligomers for Early Diagnosis and Therapy of Alzheimer's Disease

Article

作者: Rahimipour, Shai ; Tripathi, Kuldeep ; Senapati, Sudipta ; Awad, Khadeja

AbstractEarly detection and treatment are crucial for Alzheimer's disease (AD) management. Current diagnostic and therapeutic methods focus on late‐stage amyloid fibrils and plaques, overlooking toxic soluble amyloid β oligomers (AβOs) accumulating early in AD. A multifunctional liposome‐based platform is designed for early diagnosis and therapy of AD, leveraging a novel self‐assembled cyclic d,l‐α‐peptide (CP‐2) that selectively targets AβOs. Biocompatible CP‐2 conjugated liposomes (CP‐2‐LPs) effectively disrupt Aβ aggregation and mitigate Aβ‐mediated toxicity in human neuroblastoma cells. In transgenic Caenorhabditis elegans AD models, CP‐2‐LPs significantly outperformed free CP‐2 by improving cognitive and behavioral functions, extending lifespan, and reducing toxic AβO levels. Intravenous injection of fluorescently labeled CP‐2‐LPs reveals effective blood‐brain barrier penetration, with significantly higher brain fluorescence in transgenic mice than WT, enabling precise diagnosis. These findings underscore CP‐2‐LPs as a valuable tool for early detection and targeted therapy in AD.

2024-07-22·JACS Au

Gonococcal Mimitope Vaccine Candidate Forms a Beta-Hairpin Turn and Binds Hydrophobically to a Therapeutic Monoclonal Antibody

Article

作者: Ram, Sanjay ; Silipo, Alba ; Cowieson, Nathan ; Beernink, Benjamin P ; Cerofolini, Linda ; Beernink, Peter T ; Rice, Peter A ; Gulati, Sunita ; Di Carluccio, Cristina ; Carillo, Sara ; Cangiano, Alessandro ; Paduano, Luigi ; Molinaro, Antonio ; Bones, Jonathan ; Fragai, Marco ; Shaughnessy, Jutamas ; Marchetti, Roberta

The spread of multidrug-resistant strains of Neisseria gonorrhoeae, the etiologic agent of gonorrhea, represents a global health emergency. Therefore, the development of a safe and effective vaccine against gonorrhea is urgently needed. In previous studies, murine monoclonal antibody (mAb) 2C7 was raised against gonococcal lipooligosaccharide (LOS). mAb 2C7 elicits complement-dependent bactericidal activity against gonococci, and its glycan epitope is expressed by almost every clinical isolate. Furthermore, we identified a peptide, cyclic peptide 2 (CP2) that mimicked the 2C7 LOS epitope, elicited bactericidal antibodies in mice, and actively protected in a mouse vaginal colonization model. In this study, we performed structural analyses of mAb 2C7 and its complex with the CP2 peptide by X-ray crystallography, NMR spectroscopy, and molecular dynamics (MD) simulations. The crystal structure of Fab 2C7 bound to CP2 showed that the peptide adopted a beta-hairpin conformation and bound the Fab primarily through hydrophobic interactions. We employed NMR spectroscopy and MD simulations to map the 2C7 epitope and identify the bioactive conformation of CP2. We also used small-angle X-ray scattering (SAXS) and native mass spectrometry to obtain further information about the shape and assembly state of the complex. Collectively, our new structural information suggests strategies for humanizing mAb 2C7 as a therapeutic against gonococcal infection and for optimizing peptide CP2 as a vaccine antigen.

100 项与 CP-2 相关的药物交易

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