Nanoporous silica colloidal films with molecular transport gated by aptamers responsive to small molecules

We report the preparation of colloidal nanoporous silica films whose function mimics that of protein channels in gating the transport of small molecules across a cell membrane. Specifically, we report a means of controlling the molecular flux through colloidal nanopores that employ aptamer oligonucleotides binding to a specific organic small molecule (cocaine). These biomacromolecules have been introduced onto the nanopore surface by attaching pre-made oligonucleotides to the activated nanopore surface. The aptamers change their conformation in response to the binding events, and thus alter the free volume of the colloidal nanopores available for molecular transport.

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Molecular transport at cell membranes

Proceedings of the Royal Society of London Series B Biological Sciences ◽

10.1098/rspb.1965.0065 ◽

1965 ◽

Vol 163 (991) ◽

pp. 169-196 ◽

Cited By ~ 25

Keyword(s):

Cell Membrane ◽

Cell Membranes ◽

Diffusion Processes ◽

Molecular Transport ◽

Transport Processes ◽

Passive Diffusion ◽

Cell Compartment ◽

Normal Diffusion ◽

A Cell ◽

And Function

It has become increasingly evident during the last decade that cell membranes are equipped with factors that play specific roles in conveying both inorganic and organic substances from the cell exterior to the cell interior or from one compartment in the cell to another. The normal diffusion processes (often called passive diffusion) occur but these may be slow, the rates depending on the concentrations of the substances involved. Passive diffusion leads only to a concentration within the cell no higher than that outside except under circumstances where binding of the substance, to a cell constituent, takes place in the cell or in a cell compartment. The components in the cell membrane that control the rates of ionic and molecular transport, and which may lead to the attainment of concentrations of ions and molecules in the cell substantially higher than those outside, may play roles as important as those of the enzymes in the control of cell growth, metabolism and function. The process whereby a substance is transferred across the cell membrane in such a manner that it is specifically controlled, that it can lead to accumulation of the substance in the cell against a concentration gradient, and that it is energy assisted, i. e. coupled with metabolic processes, is often referred to as active transport. The specific components located at the cell membrane and involved in the transport processes are usually termed transport carriers.

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SUN-252 Rescue of Function of Inactivating Mutations in Human GPCRs in the Reproductive Hypothalamic-Pituitary-Gonadal Axis

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1724 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Robert Peter Millar

Keyword(s):

Endoplasmic Reticulum ◽

Personalized Medicine ◽

Cell Membrane ◽

Cell Surface ◽

Small Molecules ◽

Small Molecule ◽

Neurokinin B ◽

Data Bases ◽

Hpg Axis ◽

Inactivating Mutations

Abstract Inactivating mutations have been described for human GPCRs at all levels of the reproductive hypothalamic-pituitary-gonadal (HPG) axis which results in reproductive incompetence. The majority of the mutations in GPCRs give rise to misfolding and a failure to traffick to the cell surface. We have interrogated data bases for cell-permeant small molecules which bind to and stabilise the GPCR as it emerges from the endoplasmic reticulum and hence facilitate trafficking of the mutant GPCR to the cell membrane and restoration of function. In this way we have successfully ‘rescued’ function of mutant Neurokinin B, GnRH, LH and FSH receptors using small molecule antagonists which bind orthosterically or agonists which bind allosterically. These discoveries represent an advance towards novel personalized medicine for GPCR deficiencies in the human HPG axis.

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R. F. Beers, Jr. and E. G. Bassett (Editors), Cell Membrane Receptors for Viruses, Antigens and Antibodies, Polypeptide Hormones, and Small Molecules (Miles Intern. Symp. Series, No. 9). 554 S., 168 Abb., 81 Tab. New York 1976: Raven Press. $ 43.50

Zeitschrift für allgemeine Mikrobiologie ◽

10.1002/jobm.3630170612 ◽

1977 ◽

Vol 17 (6) ◽

pp. 495-495

Author(s):

W. Zschiesche

Keyword(s):

New York ◽

Cell Membrane ◽

Small Molecules ◽

Membrane Receptors ◽

Polypeptide Hormones

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Small-Molecule Targeted Aβ42 Aggregate Degradation: Negatively Charged Small Molecules Are More Promising than the Neutral Ones

ACS Chemical Neuroscience ◽

10.1021/acschemneuro.1c00047 ◽

2021 ◽

Author(s):

Jinfei Mei ◽

Huijuan Yang ◽

Bo Sun ◽

Chengqiang Liu ◽

Hongqi Ai

Keyword(s):

Small Molecules ◽

Small Molecule

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STEM-20. A CANCER STEM CELL-SELECTIVE APOPTOSIS-INDUCING SMALL MOLECULE FOR THE TREATMENT OF GBM

Neuro-Oncology ◽

10.1093/neuonc/noaa215.837 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii200-ii200

Author(s):

Stephen Skirboll ◽

Natasha Lucki ◽

Genaro Villa ◽

Naja Vergani ◽

Michael Bollong ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Small Molecules ◽

Small Molecule ◽

Large Scale ◽

Critical Role ◽

Tumor Formation ◽

Cell Type ◽

Caspase 1 ◽

Activation Assay

Abstract INTRODUCTION Glioblastoma multiforme (GBM) is the most aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation and maintenance, drug resistance, and recurrence following surgery. New therapeutic strategies for the treatment of GBM have recently focused on targeting CSCs. Here we have used an unbiased large-scale screening approach to identify drug-like small molecules that induce apoptosis in GBM CSCs in a cell type-selective manner. METHODS A luciferase-based survival assay of patient-derived GBM CSC lines was established to perform a large-scale screen of ∼one million drug-like small molecules with the goal of identifying novel compounds that are selectively toxic to chemoresistant GBM CSCs. Compounds found to kill GBM CSC lines as compared to control cell types were further characterized. A caspase activation assay was used to evaluate the mechanism of induced cell death. A xenograft animal model using patient-derived GBM CSCs was employed to test the leading candidate for suppression of in vivo tumor formation. RESULTS We identified a small molecule, termed RIPGBM, from the cell-based chemical screen that induces apoptosis in primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of RIPGBM appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an intracranial GBM xenograft mouse model, RIPGBM was found to significantly suppress tumor formation. CONCLUSIONS Our chemical genetics-based approach has identified a small molecule drug candidate and a potential drug target that selectively targets cancer stem cells and provides an approach for the treatment of GBMs.

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