Let there be light: how to use photoswitchable cross-linker to reprogram proteins

2017 ◽  
Vol 45 (3) ◽  
pp. 831-837 ◽  
Author(s):  
Daniel Hoersch
Keyword(s):  
Rational Design ◽  
Design Strategies ◽  
Molecular Tweezers ◽  
Protein Targets ◽  
Reactive Groups ◽  
Synthetic Cells ◽  
End Distance ◽  
Cross Linker ◽  
Cellular Pathways ◽  
And Function

Azobenzene is a photo-isomerizing molecule whose end-to-end distance changes upon external illumination. When combined with site-specific reactive groups, it can be used as molecular tweezers to remote-control the structure and function of protein targets. The present study gives a brief overview over the rational design strategies that use an azobenzene-based photoswitchable cross-linker to engineer ON/OFF switches into functional proteins or to reprogram proteins for novel functions. The re-engineered proteins may be used as remote controls for cellular pathways, as light-gated drug delivery platforms or as light-powered machinery of synthetic cells and micro-scaled factories.

Overview of Recent Progress in Protein-Expression Technologies for Small-Molecule Screening

2014 ◽  
Vol 19 (7) ◽  
pp. 1000-1013 ◽  
Author(s):  
John W. Cuozzo ◽  
Holly H. Soutter
Keyword(s):  
Protein Expression ◽  
Small Molecule ◽  
Posttranslational Modifications ◽  
Expression Systems ◽  
Design Strategies ◽  
Protein Targets ◽  
Small Molecule Screening ◽  
Active Research ◽  
Small Molecule Modulators ◽  
And Function

Production of novel soluble and membrane-localized protein targets for functional and affinity-based screening has often been limited by the inability of traditional protein-expression systems to generate recombinant proteins that have properties similar to those of their endogenous counterparts. Such targets have often been labeled as challenging. Although biological validation of these challenging targets for specific disease areas may be strong, discovery of small-molecule modulators can be greatly delayed or completely halted due to target-expression issues. In this article, the limitations of traditional protein-expression systems will be discussed along with new systems designed to overcome these challenges. Recent work in this field has focused on two major areas for both soluble and membrane targets: construct-design strategies to improve expression levels and new hosts that can carry out the posttranslational modifications necessary for proper target folding and function. Another area of active research has been on the reconstitution of solubilized membrane targets for both structural analysis and screening. Finally, the potential impact of these new systems on the output of small-molecule screening campaigns will be discussed.

scholarly journals Specific inhibition of the Survivin–CRM1 interaction by peptide-modified molecular tweezers

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Annika Meiners ◽  
Sandra Bäcker ◽  
Inesa Hadrović ◽  
Christian Heid ◽  
Christine Beuck ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Rational Design ◽  
Nuclear Export Signal ◽  
Signal Interference ◽  
Receptor Interaction ◽  
Dual Function ◽  
Experimental Proof ◽  
Molecular Tweezers ◽  
Recognition Element ◽  
Dynamics Simulations

AbstractSurvivin’s dual function as apoptosis inhibitor and regulator of cell proliferation is mediated via its interaction with the export receptor CRM1. This protein–protein interaction represents an attractive target in cancer research and therapy. Here, we report a sophisticated strategy addressing Survivin’s nuclear export signal (NES), the binding site of CRM1, with advanced supramolecular tweezers for lysine and arginine. These were covalently connected to small peptides resembling the natural, self-complementary dimer interface which largely overlaps with the NES. Several biochemical methods demonstrated sequence-selective NES recognition and interference with the critical receptor interaction. These data were strongly supported by molecular dynamics simulations and multiscale computational studies. Rational design of lysine tweezers equipped with a peptidic recognition element thus allowed to address a previously unapproachable protein surface area. As an experimental proof-of-principle for specific transport signal interference, this concept should be transferable to any protein epitope with a flanking well-accessible lysine.

scholarly journals Flavonoids in Skin Senescence Prevention and Treatment

2021 ◽  
Vol 22 (13) ◽  
pp. 6814
Author(s):  
Anna Domaszewska-Szostek ◽  
Monika Puzianowska-Kuźnicka ◽  
Alina Kuryłowicz
Keyword(s):  
Therapeutic Strategy ◽  
Cancer Susceptibility ◽  
Skin Aging ◽  
Structure And Function ◽  
Tissue Structure ◽  
Delayed Wound Healing ◽  
Secretory Phenotype ◽  
Cellular Pathways ◽  
And Function ◽  
Increased Susceptibility

Skin aging is associated with the accumulation of senescent cells and is related to many pathological changes, including decreased protection against pathogens, increased susceptibility to irritation, delayed wound healing, and increased cancer susceptibility. Senescent cells secrete a specific set of pro-inflammatory mediators, referred to as a senescence-associated secretory phenotype (SASP), which can cause profound changes in tissue structure and function. Thus, drugs that selectively eliminate senescent cells (senolytics) or neutralize SASP (senostatics) represent an attractive therapeutic strategy for age-associated skin deterioration. There is growing evidence that plant-derived compounds (flavonoids) can slow down or even prevent aging-associated deterioration of skin appearance and function by targeting cellular pathways crucial for regulating cellular senescence and SASP. This review summarizes the senostatic and senolytic potential of flavonoids in the context of preventing skin aging.

scholarly journals Tunable assembly of amyloid-forming peptides into nanosheets as a retrovirus carrier

2015 ◽  
Vol 112 (10) ◽  
pp. 2996-3001 ◽  
Author(s):  
Bin Dai ◽  
Dan Li ◽  
Wenhui Xi ◽  
Fang Luo ◽  
Xiang Zhang ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Rational Design ◽  
Structural Model ◽  
Amyloid Fibril ◽  
Computational Approaches ◽  
Retroviral Transduction ◽  
And Function

Using and engineering amyloid as nanomaterials are blossoming trends in bionanotechnology. Here, we show our discovery of an amyloid structure, termed “amyloid-like nanosheet,” formed by a key amyloid-forming segment of Alzheimer’s Aβ. Combining multiple biophysical and computational approaches, we proposed a structural model for the nanosheet that is formed by stacking the amyloid fibril spines perpendicular to the fibril axis. We further used the nanosheet for laboratorial retroviral transduction enhancement and directly visualized the presence of virus on the nanosheet surface by electron microscopy. Furthermore, based on our structural model, we designed nanosheet-forming peptides with different functionalities, elucidating the potential of rational design for amyloid-based materials with novel architecture and function.

scholarly journals A journey in bioinspired supramolecular chemistry: from molecular tweezers to small molecules that target myotonic dystrophy

2016 ◽  
Vol 12 ◽  
pp. 125-138 ◽  
Author(s):  
Steven C Zimmerman
Keyword(s):  
Small Molecules ◽  
Supramolecular Chemistry ◽  
Myotonic Dystrophy ◽  
Small Molecule ◽  
Early Life ◽  
Rational Design ◽  
Early Experience ◽  
Therapeutic Agents ◽  
Early Career ◽  
Molecular Tweezers

This review summarizes part of the author’s research in the area of supramolecular chemistry, beginning with his early life influences and early career efforts in molecular recognition, especially molecular tweezers. Although designed to complex DNA, these hosts proved more applicable to the field of host–guest chemistry. This early experience and interest in intercalation ultimately led to the current efforts to develop small molecule therapeutic agents for myotonic dystrophy using a rational design approach that heavily relies on principles of supramolecular chemistry. How this work was influenced by that of others in the field and the evolution of each area of research is highlighted with selected examples.

scholarly journals Polymeric micelles and molecular modeling applied to the development of radiopharmaceuticals

2012 ◽  
Vol 48 (1) ◽  
pp. 1-16 ◽  
Author(s):  
Sibila Roberta Marques Grallert ◽  
Carlota de Oliveira Rangel-Yagui ◽  
Kerly Fernanda Mesquita Pasqualoto ◽  
Leoberto Costa Tavares
Keyword(s):  
Molecular Modeling ◽  
Rational Design ◽  
Polymeric Micelles ◽  
Single Photon ◽  
Photon Emission ◽  
Disease Process ◽  
Diagnostic Techniques ◽  
Emission Computed Tomography ◽  
Amphiphilic Copolymers ◽  
Design Strategies

Micelles composed of amphiphilic copolymers linked to a radioactive element are used in nuclear medicine predominantly as a diagnostic application. A relevant advantage of polymeric micelles in aqueous solution is their resulting particle size, which can vary from 10 to 100 nm in diameter. In this review, polymeric micelles labeled with radioisotopes including technetium (99mTc) and indium (111In), and their clinical applications for several diagnostic techniques, such as single photon emission computed tomography (SPECT), gamma-scintigraphy, and nuclear magnetic resonance (NMR), were discussed. Also, micelle use primarily for the diagnosis of lymphatic ducts and sentinel lymph nodes received special attention. Notably, the employment of these diagnostic techniques can be considered a significant tool for functionally exploring body systems as well as investigating molecular pathways involved in the disease process. The use of molecular modeling methodologies and computer-aided drug design strategies can also yield valuable information for the rational design and development of novel radiopharmaceuticals.

scholarly journals Research fronts of Chemical Biology

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Shanshan Lv
Keyword(s):  
High Throughput Screening ◽  
Drug Targets ◽  
Chemical Biology ◽  
Rational Design ◽  
Future Research ◽  
Design Strategies ◽  
Binding Assays ◽  
Cellular Mechanisms ◽  
Diagnostic Technologies

Abstract Over the past decades, researchers have witnessed substantially increasing and ever-growing interests and efforts in Chemical Biology studies, thanks to the development of genome and epi-genome sequencing (revealing potential drug targets), synthetic chemistry (producing new medicines), bioorthogonal chemistry (chemistry in living systems) and high-throughput screening technologies (in vitro cell systems, protein binding assays and phenotypic assays). This report presents literature search results for current research in Chemical Biology, to explore basic principles, summarize recent advances, identify key challenges, and provide suggestions for future research (with a focus on Chemical Biology in the context of human health and diseases). Chemical Biology research can positively contribute to delivering a better understanding of the molecular and cellular mechanisms that accompany pathology underlying diseases, as well as developing improved methods for diagnosis, drug discovery, and therapeutic delivery. While much progress has been made, as shown in this report, there are still further needs and opportunities. For instance, pressing challenges still exist in selecting appropriate targets in biological systems and adopting more rational design strategies for the development of innovative and sustainable diagnostic technologies and medical treatments. Therefore, more than ever, researchers from different disciplines need to collaborate to address the challenges in Chemical Biology.

Synthesis of Nitrile-Functionalized Polydentate N-Heterocycles as Building Blocks for Covalent Triazine Frameworks

Synthesis ◽  
2021 ◽  
Author(s):  
Christian V. Stevens ◽  
Jonas Everaert ◽  
Maarten Debruyne ◽  
Flore Vanden Bussche ◽  
Kristof Van Hecke ◽  
...  
Keyword(s):  
Rational Design ◽  
Building Blocks ◽  
Heterocyclic Ligands ◽  
Support Materials ◽  
Polydentate Ligands ◽  
Catalytic Metal ◽  
Composition Structure ◽  
And Function ◽  
Application Access ◽  
Modular Nature

AbstractCovalent triazine frameworks (CTFs) based on polydentate ligands are highly promising supports to anchor catalytic metal complexes. The modular nature of CTFs allows to tailor the composition, structure, and function to its specific application. Access to a broad range of chelating building blocks is therefore essential. In this respect, we extended the current available set of CTF building blocks with new nitrile-functionalized N-heterocyclic ligands. This paper presents the synthesis of the six ligands which vary in the extent of the aromatic system and the denticity. The new building blocks may help in a rational design of enhanced support materials in catalysis.

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