Tuning Cellular Uptake of Molecular Probes by Rational Design of Their Assembly into Supramolecular Nanoprobes

2016 ◽  
Vol 138 (10) ◽  
pp. 3533-3540 ◽  
Author(s):  
Lye Lin Lock ◽  
Claudia D. Reyes ◽  
Pengcheng Zhang ◽  
Honggang Cui
Keyword(s):  
Cellular Uptake ◽  
Rational Design ◽  
Molecular Probes

scholarly journals Molecular Determinants of μ-Conotoxin KIIIA Interaction with the Voltage-Gated Sodium Channel Nav1.7

2019 ◽  
Author(s):  
Ian H. Kimball ◽  
Phuong T. Nguyen ◽  
Baldomero M. Olivera ◽  
Jon T. Sack ◽  
Vladimir Yarov-Yarovoy
Keyword(s):  
Computational Modeling ◽  
Rational Design ◽  
Structural Model ◽  
Critical Role ◽  
Structural Data ◽  
Molecular Probes ◽  
Integrative Approach ◽  
In Silico Docking ◽  
Voltage Gated ◽  
Dynamics Simulations

AbstractThe voltage-gated sodium (Nav) channel subtype Nav1.7 plays a critical role in pain signaling, making it an important drug target. Here we studied the molecular interactions between μ-conotoxin KIIIA (KIIIA) and the human Nav1.7 channel (hNav1.7). We developed a structural model of hNav1.7 using Rosetta computational modeling and performed in silico docking of KIIIA using RosettaDock to predict residues forming specific pairwise contacts between KIIIA and hNav1.7. We experimentally validated these contacts using mutant cycle analysis. Comparison between our KIIIA-hNav1.7 model and the recently published cryo-EM structure of KIIIA-hNav1.2 revealed key similarities and differences between channel subtypes with potential implications for the molecular mechanism of toxin block. Our integrative approach, combining structural data with computational modeling, experimental validation, and molecular dynamics simulations will be useful for engineering molecular probes to study Nav channel function, and for rational design of novel biologics targeting specific Nav channels.

scholarly journals Delineating the role of c-FLIP/NEMO interaction in the CD95 network via rational design of molecular probes

BMC Genomics ◽  
2019 ◽  
Vol 20 (S3) ◽  
Author(s):  
Nikita V. Ivanisenko ◽  
Jörn H. Buchbinder ◽  
Johannes Espe ◽  
Max Richter ◽  
Miriam Bollmann ◽  
...  
Keyword(s):  
Rational Design ◽  
Molecular Probes

Polyamines and novel polyamine conjugates interact with DNA in ways that can be exploited in non-viral gene therapy

2003 ◽  
Vol 31 (2) ◽  
pp. 397-406 ◽  
Author(s):  
I.S. Blagbrough ◽  
A.J. Geall ◽  
A.P. Neal
Keyword(s):  
Gene Therapy ◽  
Gene Delivery ◽  
Rational Design ◽  
Molecular Probes ◽  
Dna Condensation ◽  
Viral Gene ◽  
Viral Gene Therapy ◽  
Lipid Moiety ◽  
Polyamine Conjugates ◽  
Fluorescent Molecular Probes

As a part of our continuing studies on ‘Polyamines and their role in human disease’ we are investigating how polyamines, and especially how novel polyamine conjugates, interact with DNA. We are studying how these conjugates interact with circular plasmids in order to produce nanometre-sized particles suitable for transfecting cells. Our considerations of structure--activity relationships (SAR) within naturally occurring and synthetic polyamines have shown the significance of the inter-atomic distances between the basic nitrogen atoms. As these atoms are typically fully protonated under physiological conditions, they exist in equilibrium as polyammonium ions. The covalent addition of a lipid moiety, typically one or two alkyl or alkenyl chains, or a steroid, allows much greater efficiency in DNA condensation and in the cellular transfection achieved. Thus efficient DNA condensation and subsequently drug delivery (i.e. with DNA as the drug) can be brought about using novel polyamine conjugates. Taking further advantage of the functionalization of specific steroids (e.g. cholesterol and certain bile acids), we have designed and prepared novel fluorescent molecular probes as tools to throw light on the problematic steps in non-viral gene delivery which still impede efficient gene therapy. Thus, the current aims of our research are to understand, design and prepare small-molecule lipopolyamines for non-viral gene therapy (NVGT). The rational design and practical preparation of non-symmetrical polyamine carbamates and amides, based on steroid templates of cholesterol and the bile acid lithocholic acid as the lipid moiety, provides fluorescent molecular probes that condense DNA. These novel lipopolyamine conjugates mimic the positive charge distribution found in the triamine spermidine and the tetra-amine spermine alkaloids. After optimizing their SAR, these fluorescent probes will be useful in monitoring gene delivery in NVGT.

scholarly journals Suppression of p53 response by targeting p53-Mediator binding with a stapled peptide

2019 ◽  
Author(s):  
BL Allen ◽  
K Quach ◽  
CB Levandowski ◽  
JD Rubin ◽  
T Read ◽  
...  
Keyword(s):  
Rational Design ◽  
Human Cancer ◽  
Transcriptional Response ◽  
Molecular Probes ◽  
Activation Domains ◽  
Stapled Peptide ◽  
Human Cancer Cells ◽  
P53 Response ◽  
P53 Activation

AbstractDNA-binding transcription factors (TFs) remain challenging to target with molecular probes. Many TFs function in part through interaction with Mediator; we sought to block p53 function by disrupting the p53-Mediator interaction. Through rational design and activity-based screening, we characterized a stapled peptide, with functional mimics of both p53 activation domains, that selectively inhibited p53- and Mediator-dependent transcription in vitro. This “bivalent peptide” also suppressed p53 transcriptional response in human cancer cells. Our strategy circumvents the TF and instead targets the TF-Mediator interface, with desired transcriptional outcomes. Different TFs target Mediator through different subunits, suggesting this strategy could be broadly applied.

Rational Design of Surface-State Controlled Multicolor Cross-Linked Carbon Dots with Distinct Photoluminescence and Cellular Uptake Properties

2021 ◽  
Author(s):  
Indrajit Srivastava ◽  
Parikshit Moitra ◽  
Muhammad Fayyaz ◽  
Subhendu Pandit ◽  
Taylor L. Kampert ◽  
...  
Keyword(s):  
Cellular Uptake ◽  
Surface State ◽  
Carbon Dots ◽  
Rational Design

Rational design and fabrication of a cancer-targeted chitosan nanocarrier to enhance selective cellular uptake and anticancer efficacy of selenocystine

2015 ◽  
Vol 3 (12) ◽  
pp. 2497-2504 ◽  
Author(s):  
Bo Yu ◽  
Hong Li ◽  
Jinhui Zhang ◽  
Wenjie Zheng ◽  
Tianfeng Chen
Keyword(s):  
Cellular Uptake ◽  
Rational Design ◽  
Anticancer Efficacy

A cancer-targeted chitosan nanocarrier has been rationally designed to enhance the selective cellular uptake and anticancer efficacy of selenocystine.

scholarly journals Actinoporins: From the Structure and Function to the Generation of Biotechnological and Therapeutic Tools

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 539 ◽  
Author(s):  
Santos Ramírez-Carreto ◽  
Beatriz Miranda-Zaragoza ◽  
Claudia Rodríguez-Almazán
Keyword(s):  
Rational Design ◽  
Vaccine Development ◽  
Molecular Probes ◽  
Immunomodulatory Activity ◽  
Molecular Tools ◽  
Sea Anemones ◽  
Liposomal Formulations ◽  
Conformational Plasticity ◽  
Therapeutic Tools ◽  
And Function

Actinoporins (APs) are a family of pore-forming toxins (PFTs) from sea anemones. These biomolecules exhibit the ability to exist as soluble monomers within an aqueous medium or as constitutively open oligomers in biological membranes. Through their conformational plasticity, actinoporins are considered good candidate molecules to be included for the rational design of molecular tools, such as immunotoxins directed against tumor cells and stochastic biosensors based on nanopores to analyze unique DNA or protein molecules. Additionally, the ability of these proteins to bind to sphingomyelin (SM) facilitates their use for the design of molecular probes to identify SM in the cells. The immunomodulatory activity of actinoporins in liposomal formulations for vaccine development has also been evaluated. In this review, we describe the potential of actinoporins for use in the development of molecular tools that could be used for possible medical and biotechnological applications.

How to avoid protein aggregation to improve cellular uptake of albumin-based conjugates: towards the rational design of cell-penetrable phosphorescent probes

2018 ◽  
Vol 297 (3) ◽  
pp. 325-337 ◽  
Author(s):  
Anastasia I. Solomatina ◽  
Vadim A. Baigildin ◽  
Daniil D. Zhukovsky ◽  
Dmitrii V. Krupenya ◽  
Elena I. Koshel ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Cellular Uptake ◽  
Rational Design
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