scholarly journals Enhancing Intracellular Accumulation and Target Engagement of PROTACs with Reversible Covalent Chemistry

2019 ◽  
Author(s):  
Wen-Hao Guo ◽  
Xiaoli Qi ◽  
Xin Yu ◽  
Yang Liu ◽  
Chan-I Chung ◽  
...  
Keyword(s):  
Cellular Uptake ◽  
Kinase Inhibitor ◽  
E3 Ligase ◽  
Target Protein ◽  
Binding Affinities ◽  
Target Engagement ◽  
Intracellular Accumulation ◽  
Molecular Weights ◽  
Dual Functional ◽  
Reversible Covalent

AbstractCurrent efforts in the proteolysis targeting chimera (PROTAC) field mostly focus on choosing an appropriate E3 ligase for the target protein, improving the binding affinities towards the target protein and the E3 ligase, and optimizing the PROTAC linker. However, due to the large molecular weights of PROTACs, their cellular uptake remains an issue. Through comparing how different warhead chemistry, reversible noncovalent (RNC), reversible covalent (RC), and irreversible covalent (IRC) binders, affects the degradation of Bruton’s Tyrosine Kinase (BTK), we serendipitously discover that cyano-acrylamide-based reversible covalent chemistry can significantly enhance the intracellular accumulation and target engagement of PROTACs and develop RC-1 as a reversible covalent BTK PROTAC with a high target occupancy as its corresponding kinase inhibitor and effectiveness as a dual functional inhibitor and degrader, a different mechanism-of-action for PROTACs. Importantly, this reversible covalent strategy is generalizable to improve other PROTACs, opening a path to enhance PROTAC efficacy.

scholarly journals Enhancing intracellular accumulation and target engagement of PROTACs with reversible covalent chemistry

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Wen-Hao Guo ◽  
Xiaoli Qi ◽  
Xin Yu ◽  
Yang Liu ◽  
Chan-I Chung ◽  
...  
Keyword(s):  
Target Engagement ◽  
Intracellular Accumulation ◽  
Reversible Covalent

scholarly journals STUDY OF MAO-B INHIBITOR ANALOUGES FOR PARKINSON’S DISEASE THROUGH CADD APPROACHES

2018 ◽  
Vol 8 (5-s) ◽  
pp. 240-250
Author(s):  
Manish Bachhar ◽  
BK Singh
Keyword(s):  
Molecular Design ◽  
Neurodegenerative Disorder ◽  
Binding Mode ◽  
Docking Studies ◽  
Target Protein ◽  
Binding Affinities ◽  
Discovery Process ◽  
Drug Discovery Process ◽  
Mao B ◽  
Pharmacokinetic Properties

New derivatives are designed as target directed MAO-B Inhibitors for medical care of the patients for neurodegenerative disorder. Molecular design and estimated pharmacokinetic properties have been evaluated by using Inventus v 1.1 software. The binding mode of the proposed compounds with target protein i.e. 1S2Q was evaluated and the resulting data from docking studies explained that newly designed derivatives have high and better affinity towards target protein. Based on these properties, the binding affinities are used for speeding up drug discovery process by eliminating less potent compounds from synthesis. Keywords: MAO-B, Inventus, Target protein, Neurodegenerative, Docking.

scholarly journals In SilicoInvestigation of Potential Pyruvate Kinase M2 Regulators from Traditional Chinese Medicine against Cancers

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Kuan-Chung Chen ◽  
Kuen-Bao Chen ◽  
Hsin-Yi Chen ◽  
Calvin Yu-Chian Chen
Keyword(s):  
Virtual Screening ◽  
Drug Development ◽  
Pyruvate Kinase ◽  
Md Simulation ◽  
Docking Simulation ◽  
Target Protein ◽  
Binding Affinities ◽  
Pyruvate Kinase M2 ◽  
Lead Compounds ◽  
The Stability

A recent research in cancer research demonstrates that tumor-specific pyruvate kinase M2 (PKM2) plays an important role in chromosome segregation and mitosis progression of tumor cells. To improve the drug development of TCM compounds, we aim to identify potent TCM compounds as lead compounds of PKM2 regulators. PONDR-Fit protocol was utilized to predict the disordered disposition in the binding domain of PKM2 protein before virtual screening as the disordered structure in the protein may cause the side effect and downregulation of the possibility of ligand to bind with target protein. MD simulation was performed to validate the stability of interactions between PKM2 proteins and each ligand after virtual screening. The top TCM compounds, saussureamine C and precatorine, extracted fromLycium chinenseMill. andAbrus precatoriusL., respectively, have higher binding affinities with target protein in docking simulation than control. They have stable H-bonds with residues A:Lys311 and some other residues in both chains of PKM2 protein. Hence, we propose the TCM compounds, saussureamine C and precatorine, as potential candidates as lead compounds for further study in drug development process with the PKM2 protein against cancer.

Dual-functional carbon dots–silver@zinc oxide nanocomposite: in vitro evaluation of cellular uptake and induction of apoptosis

2015 ◽  
Vol 3 (7) ◽  
pp. 1217-1229 ◽  
Author(s):  
Abhay Sachdev ◽  
Ishita Matai ◽  
P. Gopinath
Keyword(s):  
Zinc Oxide ◽  
Cellular Uptake ◽  
Carbon Dots ◽  
In Vitro Evaluation ◽  
Dual Functional ◽  
Induction Of Apoptosis

We report here the devleopment of novel CDs decorated on a silver–zinc oxide (CD–Ag@ZnO) nanocomposite (NC) consisting of highly fluorescent CDs and Ag@ZnO.

scholarly journals Predator: A novel method for targeted protein degradation

2020 ◽  
Author(s):  
Chuanyang Liu ◽  
Jingyu Kuang ◽  
Xinyuan Qiu ◽  
Lu Min ◽  
Wenying Li ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Protein Expression ◽  
Protein Degradation ◽  
E3 Ligase ◽  
Target Protein ◽  
Receptor Interaction ◽  
Physiological Status ◽  
Ubiquitin Proteasome ◽  
Bifunctional Fusion Protein ◽  
Predator System

AbstractProtein expression and degradation are fundamental to cell function and physiological status of organisms. Interfering with protein expression not only provides powerful strategies to analyze the function of proteins but also inspires effective treatment methods for diseases caused by protein dysfunction. Recently, harnessing the power of the ubiquitin-proteasome system for targeted protein degradation (TPD) has become the focus of researches. Over the past two decades, TPD technologies, such as E3 ligase modification, PROTACs, and the Trim-Away method, have successfully re-oriented the ubiquitin-proteasome pathway and thus degraded many pathogenic proteins and even "undruggable" targets. However, A low-cost, convenient, and modularized TPD method is currently not available. Herein, we proposed a synthetic biology TPD method, termed Predator, by integrating the classic function of E3 ligase Trim21 and the expression of a bifunctional fusion protein that links Trim21 and the target protein, which leads to the formation of a ternary complex inside mammalian cells and therefore induce the ubiquitination and subsequent proteasome-dependent degradation of the target protein. We first proved this concept by using nanobody and scFv as the targeting module for the Predator system to degrade free GFP and membrane protein ErbB3, respectively. Then, we give an example of how the engineered Predator system can be developed towards biomedical solutions in the context of diabetes mellitus. Ligands-receptor interaction and adenovirus-mediated gene delivery were introduced to the Predator system, and we found this bifunctional fusion protein, in which glucagon was selected to function as the targeting module, downregulated the endogenous glucagon receptor (GCGR) and attenuated glucagon-stimulated glucose production in primary hepatocytes. Although preliminarily, our results showed that this Predator system is a highly modularized and convenient TPD method with good potential for both fundamental researches and clinical usage.Graphic abstract

scholarly journals 1-(Aminomethyl)-Trans-Cyclooct-4-Ene, a New TCO Derivative for Target Visualization and Target Engagement Measurement in Cells

2020 ◽  
Author(s):  
Cécile Echalier ◽  
Anna Rutkowska ◽  
Douglas W. Thomson ◽  
Lee Edwards ◽  
Blandine McKay ◽  
...  
Keyword(s):  
Chemical Properties ◽  
Disease Models ◽  
Binding Affinities ◽  
Amine Group ◽  
Protecting Group ◽  
Target Engagement ◽  
Broad Application ◽  
Physical Chemical ◽  
Proper Design ◽  
In Cells

Click probes have enabled a thorough study of drug interactions in relevant disease models. Proper design of the probes, including the choice of the click moiety coupled to the drug, is crucial to ensure good performance and broad application. A new <i>trans</i>-cyclooctene derivative, amTCO, was synthesised using a phthalimide protecting group as a built-in photosensitiser for the cyclooctene isomerization. The 1-(aminomethyl)-<i>trans</i>-cyclooct-4-ene (amTCO) displays a primary amine group that facilitates conjugation with carboxylic acid or hydroxyl-containing compounds. It can help tuning the physical chemical properties of the resulting probes. An amTCO probe targeting indoleamine 2,3-dioxygenase (IDO1) was superior to a TCO variant. The new probe is an effective tool for visualizing IDO1 and measuring the binding affinities of small molecule inhibitors to IDO1 in cells.

Glimpse into Cellular Internalization and Intracellular Trafficking of Lipid-Based Nanoparticles in Cancer Cells

2021 ◽  
Vol 21 ◽  
Author(s):  
Elham Kamalkazemi ◽  
Fereydoon Abedi - Gaballu ◽  
Tala Farid Mohammad Hosseini ◽  
Ali Mohammadi ◽  
Behzad Mansoori ◽  
...  
Keyword(s):  
Particle Size ◽  
Cancer Cells ◽  
Cellular Uptake ◽  
Therapeutic Agents ◽  
Cellular Internalization ◽  
Intracellular Accumulation ◽  
Coated Nanoparticles ◽  
Cargo Delivery ◽  
Anti Cancer ◽  
Intracellular Fate

: Lipid-based nanoparticles as drug delivery carriers have been mainly used for delivery of anti-cancer therapeutic agents. Lipid-based nanoparticles, due to their smaller particle size and similarity to cell membranes, are readily internalized into cancer cells. Interestingly, cancer cells also overexpress receptors for specific ligands including folic acid, hyaluronic acid, and transferrin on their surface. This allows the use of these ligands for surface modification of the lipid-based nanoparticle. These modifications then allow the specific recognition of these ligand-coated nanoparticles by their receptors on cancer cells allowing the targeted gradual intracellular accumulation of the functionalized nanoplatforms. These interactions could eventually enhance the internalization of desired drugs via increasing ligand-receptor mediated cellular uptake of the nanoplatforms. The cellular internalization of the nanoplatforms also varies and depends on their physicochemical properties including particle size, zeta potential, and shape. The cellular uptake is also influenced by the types of ligand internalization pathway utilized by cells such as phagocytosis, macropinocytosis, and multiple endocytosis pathways. In this review, we will classify and discuss lipid based nanoparticles engineered to express specific ligands, and are recognized by their receptors on cancer cell, and their cellular internalization pathways. Moreover, the intracellular fate of nanoparticles decorated with specific ligands and the best internalization pathways (caveolae mediated endocytosis) for safe cargo delivery will be discussed.

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