A general model of multivalent binding with ligands of heterotypic subunits and multiple surface receptors

10.1101/2021.03.10.434776 ◽

2021 ◽

Author(s):

Zhixin Cyrillus Tan ◽

Aaron S. Meyer

Keyword(s):

Large Scale ◽

Cell Communication ◽

Rational Drug Design ◽

Cell Surface Receptor ◽

Computationally Efficient ◽

Binding Model ◽

Surface Receptors ◽

Surface Receptor ◽

Multivalent Binding ◽

Multiple Ligands

AbstractMultivalent cell surface receptor binding is a ubiquitous biological phenomenon with functional and therapeutic significance. Predicting the amount of ligand binding for a cell remains an important question in computational biology as it can provide great insight into cell-to-cell communication and rational drug design toward specific targets. In this study, we extend a mechanistic, two-step multivalent binding model to account for multiple ligands and receptors, optionally allowing heterogeneous complexes. We derive the macroscopic pre-dictions for both specifically arranged and randomly assorted complexes, and demonstrate how this model enables large-scale predictions on mixture binding and the binding space of a ligand. This model provides an elegant and computationally efficient framework for analyzing multivalent binding.

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Intralysosomal Accumulation of Colloidal Gold-Low Density Lipoprotein Conjugates in Chloroquine-Treated Fibroblasts

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010011951x ◽

1985 ◽

Vol 43 ◽

pp. 546-547 ◽

Cited By ~ 1

Author(s):

Dean A. Handley ◽

Cynthia M. Arbeeny ◽

Larry D. Witte

Keyword(s):

Colloidal Gold ◽

Cultured Cells ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Coated Vesicle ◽

Low Density ◽

Cholesterol Esters ◽

Cultured Fibroblasts ◽

Surface Receptors ◽

Ldl Particles

Low density lipoproteins (LDL) are the major cholesterol carrying particles in the blood. Using cultured cells, it has been shown that LDL particles interact with specific surface receptors and are internalized via a coated pit-coated vesicle pathway for lysosomal catabolism. This (Pathway has been visualized using LDL labeled to ferritin or colloidal gold. It is now recognized that certain lysomotropic agents, such as chloroquine, inhibit lysosomal enzymes that degrade protein and cholesterol esters. By interrupting cholesterol ester hydrolysis, chloroquine treatment results in lysosomal accumulation of cholesterol esters from internalized LDL. Using LDL conjugated to colloidal gold, we have examined the ultrastructural effects of chloroquine on lipoprotein uptake by normal cultured fibroblasts.

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Ultra high resolution SEM at high voltage images individual fab fragments applied as molecular label to cell surface receptors

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010015232x ◽

1989 ◽

Vol 47 ◽

pp. 70-71

Author(s):

Klaus-Ruediger Peters

Keyword(s):

High Resolution ◽

High Energy ◽

Metal Coating ◽

Beam Diameter ◽

Surface Receptors ◽

Surface Mobility ◽

Metal Atoms ◽

Shadowing Effect ◽

Imaging Mode ◽

Deposition Techniques

Topographic ultra high resolution can now routinely be established on bulk samples in cold field emission scanning electron microscopy with a second generation of microscopes (FSEM) designed to provide 0.5 nm probe diameters. If such small probes are used for high magnification imaging, topographic contrast is so high that remarkably fine details can be imaged on 2DMSO/osmium-impregnated specimens at ribosome surfaces even without a metal coating. On TCH/osmium-impregnated specimens topographic resolution can be increased further if the SE-I imaging mode is applied. This requires that beam diameter and metal coating thickness be made smaller than the SE range of ~1 nm and background signal contributions be reduced. Subnanometer small probes can be obtained (only) at high accelerating voltages. Subnanometer thin continuous metal films can be produced under the following conditions: self-shadowing effect between metal atoms must be reduced through appropriate deposition techniques and surface mobility of metal atoms must be diminished through high energy sputtering and/or specimen cooling.

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Extracellular matrix: the gatekeeper of tumor angiogenesis

Biochemical Society Transactions ◽

10.1042/bst20190653 ◽

2019 ◽

Vol 47 (5) ◽

pp. 1543-1555 ◽

Cited By ~ 10

Author(s):

Maurizio Mongiat ◽

Simone Buraschi ◽

Eva Andreuzzi ◽

Thomas Neill ◽

Renato V. Iozzo

Keyword(s):

Extracellular Matrix ◽

Tumor Angiogenesis ◽

Signaling Cascades ◽

Cancer Growth ◽

Cell Behavior ◽

Metastatic Progression ◽

Surface Receptors ◽

The Matrix ◽

Multiple Signaling

Abstract The extracellular matrix is a network of secreted macromolecules that provides a harmonious meshwork for the growth and homeostatic development of organisms. It conveys multiple signaling cascades affecting specific surface receptors that impact cell behavior. During cancer growth, this bioactive meshwork is remodeled and enriched in newly formed blood vessels, which provide nutrients and oxygen to the growing tumor cells. Remodeling of the tumor microenvironment leads to the formation of bioactive fragments that may have a distinct function from their parent molecules, and the balance among these factors directly influence cell viability and metastatic progression. Indeed, the matrix acts as a gatekeeper by regulating the access of cancer cells to nutrients. Here, we will critically evaluate the role of selected matrix constituents in regulating tumor angiogenesis and provide up-to-date information concerning their primary mechanisms of action.

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Nanotheranostic agents for neurodegenerative diseases

Emerging Topics in Life Sciences ◽

10.1042/etls20190141 ◽

2020 ◽

Vol 4 (6) ◽

pp. 645-675

Author(s):

Parasuraman Padmanabhan ◽

Mathangi Palanivel ◽

Ajay Kumar ◽

Domokos Máthé ◽

George K. Radda ◽

...

Keyword(s):

Drug Delivery ◽

Neurodegenerative Diseases ◽

Cell Types ◽

Specific Cell ◽

Ageing Population ◽

Target Tissue ◽

Therapeutic Approaches ◽

Surface Receptors ◽

Theranostic Agents ◽

Preclinical Animal Models

Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), affect the ageing population worldwide and while severely impairing the quality of life of millions, they also cause a massive economic burden to countries with progressively ageing populations. Parallel with the search for biomarkers for early detection and prediction, the pursuit for therapeutic approaches has become growingly intensive in recent years. Various prospective therapeutic approaches have been explored with an emphasis on early prevention and protection, including, but not limited to, gene therapy, stem cell therapy, immunotherapy and radiotherapy. Many pharmacological interventions have proved to be promising novel avenues, but successful applications are often hampered by the poor delivery of the therapeutics across the blood-brain-barrier (BBB). To overcome this challenge, nanoparticle (NP)-mediated drug delivery has been considered as a promising option, as NP-based drug delivery systems can be functionalized to target specific cell surface receptors and to achieve controlled and long-term release of therapeutics to the target tissue. The usefulness of NPs for loading and delivering of drugs has been extensively studied in the context of NDDs, and their biological efficacy has been demonstrated in numerous preclinical animal models. Efforts have also been made towards the development of NPs which can be used for targeting the BBB and various cell types in the brain. The main focus of this review is to briefly discuss the advantages of functionalized NPs as promising theranostic agents for the diagnosis and therapy of NDDs. We also summarize the results of diverse studies that specifically investigated the usage of different NPs for the treatment of NDDs, with a specific emphasis on AD and PD, and the associated pathophysiological changes. Finally, we offer perspectives on the existing challenges of using NPs as theranostic agents and possible futuristic approaches to improve them.

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