scholarly journals Opportunities and Challenges of Small Molecule Induced Targeted Protein Degradation

2021 ◽  
Vol 9 ◽  
Author(s):  
Ming He ◽  
Wenxing Lv ◽  
Yu Rao
Keyword(s):  
Rna Interference ◽  
Protein Degradation ◽  
Small Molecules ◽  
Small Molecule ◽  
Gene Editing ◽  
Small Molecule Inhibitors ◽  
Tumor Resistance ◽  
Target Proteins ◽  
Enzymatic Function ◽  
New Type

Proteolysis targeting chimeras (PROTAC) represents a new type of small molecule induced protein degradation technology that has emerged in recent years. PROTAC uses bifunctional small molecules to induce ubiquitination of target proteins and utilizes intracellular proteasomes for chemical knockdown. It complements the gene editing and RNA interference for protein knockdown. Compared with small molecule inhibitors, PROTAC has shown great advantages in overcoming tumor resistance, affecting the non-enzymatic function of target proteins, degrading undruggable targets, and providing new rapid and reversible chemical knockout tools. At the same time, its challenges and problems also need to be resolved as a fast-developing newchemical biology technology.

Small-molecule degraders of cyclin-dependent kinase protein: a review

2021 ◽  
Author(s):  
Bin Yu ◽  
Zekun Du ◽  
Yuming Zhang ◽  
Zhiyu Li ◽  
Jinlei Bian
Keyword(s):  
Cell Cycle ◽  
Drug Resistance ◽  
Protein Degradation ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Structural Characteristics ◽  
Protein A ◽  
Cyclin Dependent Kinase ◽  
Chemical Tools ◽  
Potential Therapeutics

Proteolysis-targeting chimeras are a new modality of chemical tools and potential therapeutics involving the induction of protein degradation. Cyclin-dependent kinase (CDK) protein, which is involved in cycles and transcription cycles, participates in regulation of the cell cycle, transcription and splicing. Proteolysis-targeting chimeras targeting CDKs show several advantages over traditional CDK small-molecule inhibitors in potency, selectivity and drug resistance. In addition, the discovery of molecule glues promotes the development of CDK degraders. Herein, the authors describe the existing CDK degraders and focus on the discussion of the structural characteristics and design of these degraders.

scholarly journals Discovery and mechanism of action of small molecule inhibitors of ceramidases

2021 ◽  
Author(s):  
Sebastien Granier ◽  
Robert D Healey ◽  
Essa Saied ◽  
Xiaojing Cong ◽  
Gergely Karsai ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Small Molecules ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Integral Membrane Proteins ◽  
Sphingolipid Metabolism ◽  
New Paradigm ◽  
Biophysical Characterization ◽  
Sphingosine 1 Phosphate

Sphingolipid metabolism is tightly controlled by enzymes to regulate essential processes such as energy utilisation and cell proliferation. The central metabolite is ceramide, a pro-apoptotic lipid catabolized by ceramidase enzymes to ultimately produce pro-proliferative sphingosine-1-phosphate. Human ceramidases can be soluble proteins (acid and neutral ceramidase) or integral membrane proteins (alkaline ceramidases). Increasing ceramide levels to increase apoptosis has shown efficacy as a cancer treatment using small molecules inhibiting a soluble ceramidase. Due to the transmembrane nature of alkaline ceramidases, no specific small molecule inhibitors have been reported. Here, we report novel fluorescent substrates (FRETceramides) of ceramidases that can be used to monitor enzyme activity in real-time. We use FRETceramides to discover the first drug-like inhibitors of alkaline ceramidase 3 (ACER3) which are active in cell-based assays. Biophysical characterization of enzyme:inhibitor interactions reveal a new paradigm for inhibition of lipid metabolising enzymes with non-lipidic small molecules.

scholarly journals Identification of small molecule inhibitors of the Lin28-mediated blockage of pre-let-7g processing

2016 ◽  
Vol 14 (43) ◽  
pp. 10208-10216 ◽  
Author(s):  
Helen L. Lightfoot ◽  
Eric A. Miska ◽  
Shankar Balasubramanian
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Mirna Precursor

Small molecules enhance Dicer processing of a let-7 miRNA precursor through antagonization of the Lin28–pre-let-7 interaction.

scholarly journals Small molecule inhibitors of arginyltransferase regulate arginylation-dependent protein degradation, cell motility, and angiogenesis

2012 ◽  
Vol 83 (7) ◽  
pp. 866-873 ◽  
Author(s):  
Sougata Saha ◽  
Junling Wang ◽  
Brian Buckley ◽  
Qingqing Wang ◽  
Brenda Lilly ◽  
...  
Keyword(s):  
Cell Motility ◽  
Protein Degradation ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Dependent Protein

scholarly journals The First Small-Molecule Inhibitors of Members of the Ribonuclease E Family

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Louise Kime ◽  
Helen A. Vincent ◽  
Deena M. A. Gendoo ◽  
Stefanie S. Jourdan ◽  
Colin W. G. Fishwick ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Small Molecules ◽  
Small Molecule ◽  
High Throughput Screening ◽  
Small Molecule Inhibitors ◽  
Rnase E ◽  
Ribonuclease E ◽  
New Antibiotics ◽  
Drug Leads ◽  
Number Of Bacteria

Abstract The Escherichia coli endoribonuclease RNase E is central to the processing and degradation of all types of RNA and as such is a pleotropic regulator of gene expression. It is essential for growth and was one of the first examples of an endonuclease that can recognise the 5′-monophosphorylated ends of RNA thereby increasing the efficiency of many cleavages. Homologues of RNase E can be found in many bacterial families including important pathogens, but no homologues have been identified in humans or animals. RNase E represents a potential target for the development of new antibiotics to combat the growing number of bacteria that are resistant to antibiotics in use currently. Potent small molecule inhibitors that bind the active site of essential enzymes are proving to be a source of potential drug leads and tools to dissect function through chemical genetics. Here we report the use of virtual high-throughput screening to obtain small molecules predicted to bind at sites in the N-terminal catalytic half of RNase E. We show that these compounds are able to bind with specificity and inhibit catalysis of Escherichia coli and Mycobacterium tuberculosis RNase E and also inhibit the activity of RNase G, a paralogue of RNase E.

scholarly journals Targeting epigenetic protein–protein interactions with small-molecule inhibitors

2020 ◽  
Vol 12 (14) ◽  
pp. 1305-1326 ◽  
Author(s):  
Brian M Linhares ◽  
Jolanta Grembecka ◽  
Tomasz Cierpicki
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Protein Interactions ◽  
Small Molecule Inhibitors ◽  
Chemical Space ◽  
Scaffolding Proteins ◽  
Protein Protein Interactions ◽  
Post Translational Modifications ◽  
Inhibitor Development ◽  
Interdisciplinary Approaches

Epigenetic protein–protein interactions (PPIs) play essential roles in regulating gene expression, and their dysregulations have been implicated in many diseases. These PPIs are comprised of reader domains recognizing post-translational modifications on histone proteins, and of scaffolding proteins that maintain integrities of epigenetic complexes. Targeting PPIs have become focuses for development of small-molecule inhibitors and anticancer therapeutics. Here we summarize efforts to develop small-molecule inhibitors targeting common epigenetic PPI domains. Potent small molecules have been reported for many domains, yet small domains that recognize methylated lysine side chains on histones are challenging in inhibitor development. We posit that the development of potent inhibitors for difficult-to-prosecute epigenetic PPIs may be achieved by interdisciplinary approaches and extensive explorations of chemical space.

scholarly journals A Time-Resolved Fluorescence Assay to Identify Small-Molecule Inhibitors of HIV-1 Fusion

2007 ◽  
Vol 12 (6) ◽  
pp. 865-874 ◽  
Author(s):  
Géry Dams ◽  
Koen Van Acker ◽  
Emmanuel Gustin ◽  
Inge Vereycken ◽  
Lieve Bunkens ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Protein Interactions ◽  
High Throughput Screening ◽  
Small Molecule Inhibitors ◽  
Coiled Coil ◽  
Heptad Repeat ◽  
Time Resolved ◽  
Helix Bundle ◽  
Hiv 1

Fusion of host cell and human immunodeficiency virus type 1 (HIV-1) membranes is mediated by the 2 “heptad-repeat” regions of the viral gp41 protein. The collapse of the C-terminal heptad-repeat regions into the hydrophobic grooves of a coiled-coil formed by the corresponding homotrimeric N-terminal heptad-repeat regions generates a stable 6-helix bundle. This brings viral and cell membranes together for membrane fusion, facilitating viral entry. The authors developed an assay based on soluble peptides derived from the gp41 N-terminal heptad-repeat region (IQN36) as well as from the C-terminal region (C34). Both peptides were labeled with fluorophores, IQN36 with allophycocyanin (APC) and C34 with the lanthanide europium (Eu3+). Formation of the 6-helix bundle brings both fluorophores in close proximity needed for Förster resonance energy transfer (FRET). Compounds that interfere with binding of C34-Eu with IQN36-APC suppress the FRET signal. The assay was validated with various peptides and small molecules, and quenching issues were addressed. Evaluation of a diversified compound collection in a high-throughput screening campaign enabled identification of small molecules with different chemical scaffolds that inhibit this crucial intermediate in the HIV-1 entry process. This study's observations substantiate the expediency of time-resolved FRET-based assays to identify small-molecule inhibitors of protein-protein interactions. ( Journal of Biomolecular Screening 2007:865-874)

scholarly journals Prediction of small molecule inhibitors targeting the novel coronavirus (SARS-CoV-2) RNA-dependent RNA polymerase

2020 ◽  
Author(s):  
Mohammed Ahmed ◽  
Abhisek Dwivedy ◽  
Richard Mariadasse ◽  
Satish Tiwari ◽  
Jeyaraman Jeyakanthan ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Small Molecules ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Viral Proteins ◽  
The Novel ◽  
Rna Dependent Rna Polymerase ◽  
Computational Tools ◽  
Gtp Binding ◽  
Novel Coronavirus

The current COVID-19 outbreak calls for a multi-disciplinary approach towards the design and development of novel anti-COVID therapeutics including vaccines and small molecule inhibitors targeting the viral proteins of causative agent, SARS-CoV-2. Using a combination of bioinformatics and computational tools, we have modelled the 3-D structure of the RNA-dependent RNA-polymerase (RdRp) of SARS-CoV-2 and predicted its probable GTP-binding site. This site was computationally targeted using small molecules inhibitors reported in a previous study on the RdRp of the Hepatitis C virus. Further optimizations have suggested a lead molecule that may prove fruitful in development of inhibitors against RdRp of SARS-CoV-2.

scholarly journals Anti-Virulence Strategy against the Honey Bee Pathogenic Bacterium Paenibacillus larvae via Small Molecule Inhibitors of the Bacterial Toxin Plx2A

Toxins ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 607
Author(s):  
Julia Ebeling ◽  
Franziska Pieper ◽  
Josefine Göbel ◽  
Henriette Knispel ◽  
Michael McCarthy ◽  
...  
Keyword(s):  
Small Molecules ◽  
Honey Bee ◽  
Small Molecule ◽  
Bacterial Infections ◽  
Small Molecule Inhibitors ◽  
Paenibacillus Larvae ◽  
Bacterial Toxin ◽  
American Foulbrood ◽  
Honey Bee Larvae

American Foulbrood, caused by Paenibacillus larvae, is the most devastating bacterial honey bee brood disease. Finding a treatment against American Foulbrood would be a huge breakthrough in the battle against the disease. Recently, small molecule inhibitors against virulence factors have been suggested as candidates for the development of anti-virulence strategies against bacterial infections. We therefore screened an in-house library of synthetic small molecules and a library of flavonoid natural products, identifying the synthetic compound M3 and two natural, plant-derived small molecules, Acacetin and Baicalein, as putative inhibitors of the recently identified P. larvae toxin Plx2A. All three inhibitors were potent in in vitro enzyme activity assays and two compounds were shown to protect insect cells against Plx2A intoxication. However, when tested in exposure bioassays with honey bee larvae, no effect on mortality could be observed for the synthetic or the plant-derived inhibitors, thus suggesting that the pathogenesis strategies of P. larvae are likely to be too complex to be disarmed in an anti-virulence strategy aimed at a single virulence factor. Our study also underscores the importance of not only testing substances in in vitro or cell culture assays, but also testing the compounds in P. larvae-infected honey bee larvae.

Sign in / Sign up

Export Citation Format

Share Document