scholarly journals A beginner’s guide to PROTACs and targeted protein degradation

2021 ◽  
Author(s):  
Alessio Ciulli ◽  
Nicole Trainor
Keyword(s):  
Protein Degradation ◽  
Waste Disposal ◽  
E3 Ligase ◽  
Proteasomal Degradation ◽  
Target Protein ◽  
Keen Interest ◽  
Drug Candidates ◽  
The World ◽  
New Type ◽  
Chemical Tools

Those with a keen interest in targeting proteins, from chemical biologists to drug hunters alike, cannot help but take notice that a new type of molecule is making waves across this research space. Proteolysis Targeting Chimeras (or PROTACs) are protein degraders, which utilize the cell’s own waste disposal machinery to eliminate instead of inhibit a target protein. The key to PROTACs is their bifunctionality: they simultaneously bind a target protein and an E3 ligase protein, which then ubiquitylates the target, marking it for proteasomal degradation. This concept originated in the late 1990s and the first PROTAC was reported in 2001 by the laboratories of Craig Crews and Raymond Deshaies. However, interest in PROTACs did not pick up until 2015 when improved molecules were developed by the laboratories of Jay Bradner, Alessio Ciulli and Craig Crews. Ever since, PROTACs and the wider field of targeted protein degradation have expanded exponentially, with many groups around the world developing degraders as chemical tools to study proteins and as drug candidates for the treatment of diseases.

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 Perspectives on the development of first-in-class protein degraders

2021 ◽  
Author(s):  
Kalyn M Rambacher ◽  
Matthew F Calabrese ◽  
Masaya Yamaguchi
Keyword(s):  
Protein Degradation ◽  
E3 Ligase ◽  
Ubiquitin Proteasome System ◽  
26S Proteasome ◽  
Target Protein ◽  
Protein Homeostasis ◽  
Recent Advances ◽  
Subsequent Degradation ◽  
Ubiquitin Proteasome

Targeted protein degradation is a broad and expanding field aimed at the modulation of protein homeostasis. A focus of this field has been directed toward molecules that hijack the ubiquitin proteasome system with heterobifunctional ligands that recruit a target protein to an E3 ligase to facilitate polyubiquitination and subsequent degradation by the 26S proteasome. Despite the success of these chimeras toward a number of clinically relevant targets, the ultimate breadth and scope of this approach remains uncertain. Here we highlight recent advances in assays and tools available to evaluate targeted protein degradation, including and beyond the study of E3-targeted chimeric ligands. We note several challenges associated with degrader development and discuss various approaches to expanding the protein homeostasis toolbox.

scholarly journals Covalent Ligand Screening Uncovers a RNF4 E3 Ligase Recruiter for Targeted Protein Degradation Applications

2018 ◽  
Author(s):  
Carl C. Ward ◽  
Jordan I. Kleinman ◽  
Scott M. Brittain ◽  
Patrick S. Lee ◽  
Clive Yik Sham Chung ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Protein Targeting ◽  
E3 Ligase ◽  
Proteasomal Degradation ◽  
Protein Profiling ◽  
Dependent Manner ◽  
E3 Ligases ◽  
Ligand Screening ◽  
Bromodomain Proteins ◽  
Screening Approaches

AbstractTargeted protein degradation has arisen as a powerful strategy for drug discovery allowing the targeting of undruggable proteins for proteasomal degradation. This approach most often employs heterobifunctional degraders consisting of a protein-targeting ligand linked to an E3 ligase recruiter to ubiquitinate and mark proteins of interest for proteasomal degradation. One challenge with this approach, however, is that only few E3 ligase recruiters currently exist for targeted protein degradation applications, despite the hundreds of known E3 ligases in the human genome. Here, we utilized activity-based protein profiling (ABPP)-based covalent ligand screening approaches to identify cysteine-reactive small-molecules that react with the E3 ubiquitin ligase RNF4 and provide chemical starting points for the design of RNF4-based degraders. The hit covalent ligand from this screen reacted with either of two zinc-coordinating cysteines in the RING domain, C132 and C135, with no effect on RNF4 activity. We further optimized the potency of this hit and incorporated this potential RNF4 recruiter into a bifunctional degrader linked to JQ1, an inhibitor of the BET family of bromodomain proteins. We demonstrate that the resulting compound CCW 28-3 is capable of degrading BRD4 in a proteasome- and RNF4-dependent manner. In this study, we have shown the feasibility of using chemoproteomics-enabled covalent ligand screening platforms to expand the scope of E3 ligase recruiters that can be exploited for targeted protein degradation applications.

scholarly journals In vivo target protein degradation induced by PROTACs based on E3 ligase DCAF15

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Liang Li ◽  
Dazhao Mi ◽  
Haixiang Pei ◽  
Qiuhui Duan ◽  
Xinyue Wang ◽  
...  
Keyword(s):  
Protein Degradation ◽  
E3 Ligase ◽  
Target Protein

COVID 19: REALS AND CHALLENGES AGAINST DOCTORS

2020 ◽  
Vol 2 (1) ◽  
pp. 65-87
Author(s):  
Zen Ahmad
Keyword(s):  
Virus Disease ◽  
Clinical Manifestations ◽  
World Health ◽  
Unknown Etiology ◽  
Wuhan City ◽  
Traditional Markets ◽  
Pneumonia Case ◽  
The World ◽  
New Type ◽  
Health Organization

Corona Virus Disease (Covid-19) is a contagious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) which was discovered in December 2019 in China. This disease can cause clinical manifestations in the airway, lung and systemic. The World Health Organization (WHO) representative of China reported a pneumonia case with unknown etiology in Wuhan City, Hubei Province, China on December 31, 2019. The cause was identified as a new type of coronavirus on January 7, 2020 with an estimated source of the virus from traditional markets (seafood market). ) Wuhan city

A Caged E3 Ligase Ligand for PROTAC-Mediated Protein Degradation with Light

2019 ◽  
Author(s):  
Cyrille Kounde ◽  
Maria M. Shchepinova ◽  
Edward Tate
Keyword(s):  
Protein Degradation ◽  
Irradiation Time ◽  
E3 Ligase ◽  
Von Hippel Lindau ◽  
Short Irradiation ◽  
Short Irradiation Time ◽  
Spatiotemporal Control

A caging group has been appended to a widely used Von Hippel Lindau (VHL) E3 ligase ligand for targeted protein degradation with PROTACs. Proteolysis is triggered only after a short irradiation time allowing spatiotemporal control of the protein’s fate.

PHOTACs Enable Optical Control of Protein Degradation

2019 ◽  
Author(s):  
Martin Reynders ◽  
Bryan Matsuura ◽  
Marleen Bérouti ◽  
Daniele Simoneschi ◽  
Antonio Marzio ◽  
...  
Keyword(s):  
Protein Degradation ◽  
E3 Ligase ◽  
Optical Control ◽  
Cellular Proteins ◽  
Bifunctional Molecules ◽  
Protein Levels ◽  
Lead Compounds ◽  
Subsequent Degradation ◽  
Temporal And Spatial ◽  
Precision Therapeutics

<p><i>PROTACs (proteolysis targeting chimeras) are bifunctional molecules that tag proteins for ubiquitylation by an E3 ligase complex and subsequent degradation by the proteasome. They have emerged as powerful tools to control the levels of specific cellular proteins and are on the verge of being clinically used. We now introduce photoswitchable PROTACs that can be activated with the temporal and spatial precision that light provides. These trifunctional molecules, which we named PHOTACs, consist of a ligand for an E3 ligase, a photoswitch, and a ligand for a protein of interest. We demonstrate this concept by using PHOTACs that target either BET family proteins (BRD2,3,4) or FKBP12. Our lead compounds display little or no activity in the dark but can be reversibly activated to varying degrees with different wavelengths of light. Our modular and generalizable approach provides a method for the optical control of protein levels with photopharmacology and could lead to new types of precision therapeutics that avoid undesired systemic toxicity.</i><b></b></p>

Myths about COVID-19

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 907-912
Author(s):  
Deepika Masurkar ◽  
Priyanka Jaiswal
Keyword(s):  
World Health ◽  
Indian Society ◽  
Common People ◽  
The World ◽  
New Type ◽  
The Media ◽  
Personal Level ◽  
Novel Virus ◽  
The Common ◽  
Health Organization

Recently at the end of 2019, a new disease was found in Wuhan, China. This disease was diagnosed to be caused by a new type of coronavirus and affected almost the whole world. Chinese researchers named this novel virus as 2019-nCov or Wuhan-coronavirus. However, to avoid misunderstanding the World Health Organization noises it as COVID-19 virus when interacting with the media COVID-19 is new globally as well as in India. This has disturbed peoples mind. There are various rumours about the coronavirus in Indian society which causes panic in peoples mind. It is the need of society to know myths and facts about coronavirus to reduce the panic and take the proper precautionary actions for our safety against the coronavirus. Thus this article aims to bust myths and present the facts to the common people. We need to verify myths spreading through social media and keep our self-ready with facts so that we can protect our self in a better way. People must prevent COVID 19 at a personal level. Appropriate action in individual communities and countries can benefit the entire world.

Performance of 4G-LTE Communication and Navigation System in Blended Wing-Body UAS

2019 ◽  
Vol 8 (4) ◽  
pp. 9538-9542
Keyword(s):  
Satellite Communication ◽  
Line Of Sight ◽  
Multiple Factors ◽  
The World ◽  
New Type ◽  
Blended Wing Body ◽  
4G Lte ◽  
The Right ◽  
And Control ◽  
Technology Demonstrator

In vision of searching for the right Unmanned Aerial System (UAS) for a specific mission, there are multiple factors to be considered by the operator such as mission, endurance, type of payload and range of the telemetry and control. This research is focusing on extending control range of the UAS by using 4G-LTE network to enable beyond-line-of-sight flying for the commercial UAS. Major UAS such Global Hawk, Predator MQ-1 are able to fly thousands of kilometers by the use of satellite communication. However, the satellite communication annual license subscription can be very expensive. With this situation in mind, a new type of flight controller with 4G-LTE communication has been developed and tested. Throughout the research, blended-wing-body (BWB) Baseline B2S is used as the platform for technology demonstrator. Result from this analysis has proven that the proposed system is capable to control a UAS from as far as United Kingdom, with a latency less than 881 ms in average. The new added capability can potentially give the commercial UAS community a new horizon to be able to control their UAS from anywhere around the world with the availability of 4G-LTE connection

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