In Vitro and Cellular Probes to Study PARP Enzyme Target Engagement.

Cell Chemical Biology
Tim J WigleKevin W Kuntz

Abstract

Poly(ADP-ribose) polymerase (PARP) enzymes use nicotinamide adenine dinucleotide (NAD+) to modify up to seven different amino acids with a single mono(ADP-ribose) unit (MARylation deposited by PARP monoenzymes) or branched poly(ADP-ribose) polymers (PARylation deposited by PARP polyenzymes). To enable the development of tool compounds for PARP monoenzymes and polyenzymes, we have developed active site probes for use in in vitro and cellular biophysical assays to characterize active site-directed inhibitors that compete for NAD+ binding. These assays are agnostic of the protein substrate for each PARP, overcoming a general lack of knowledge around the substrates for these enzymes. The in vitro assays use less enzyme than previously described activity assays, enabling discrimination of inhibitor potencies in the single-digit nanomolar range, and the cell-based assays can differentiate compounds with sub-nanomolar potencies and measure inhibitor residence time in live cells.

References

Jun 6, 2000·Journal of Biomolecular Screening·J H ZhangK R Oldenburg
Jul 24, 2007·Journal of Biomolecular Screening·Connie S LebakkenKurt W Vogel
Jun 15, 2011·Analytical Biochemistry·Robert A CopelandMargaret Porter Scott
Feb 22, 2012·Nature Biotechnology·Elisabet WahlbergJohan Weigelt
Jun 5, 2012·The Journal of Biological Chemistry·Tobias KarlbergHerwig Schüler
Nov 3, 2012·Cancer Research·Junko MuraiYves Pommier
Jan 22, 2013·Cell Communication and Signaling : CCS·Karla Lh FeijsBernhard Lüscher
Mar 15, 2013·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Harikanth VenkannagariLari Lehtiö
Jun 8, 2013·ACS Chemical Biology·Anders E G LindgrenHerwig Schüler
Jun 6, 2014·Nature Reviews. Cancer·Sejal Vyas, Paul Chang
Jun 6, 2014·ACS Medicinal Chemistry Letters·Teemu HaikarainenLari Lehtiö
Jul 1, 2014·Current Pharmaceutical Design·Teemu HaikarainenLari Lehtio
Jul 22, 2014·Nature Communications·Sejal VyasPaul Chang
May 27, 2015·ACS Chemical Biology·Thomas MachleidtKeith V Wood
Oct 2, 2015·Cells·Mareike BütepageBernhard Lüscher
Nov 8, 2015·Bioorganic & Medicinal Chemistry Letters·Jeffrey W JohannesDavid A Scott
Dec 4, 2015·Nature Communications·Matthew B RobersKeith V Wood
Dec 19, 2015·Nature Reviews. Drug Discovery·Robert A Copeland
Jan 18, 2016·Cell Reports·Ian Carter-O'ConnellMichael S Cohen
Aug 16, 2016·Nature Reviews. Drug Discovery·Jean-Paul RenaudHerbert Nar
Dec 6, 2016·Angewandte Chemie·Bo PengShao Q Yao
Dec 22, 2016·Journal of Medicinal Chemistry·Ann-Gerd ThorsellHerwig Schüler
Mar 21, 2017·Biochemical and Biophysical Research Communications·Mariko Yoneyama-HirozaneTomohiro Kawamoto
May 20, 2017·Molecular Cell·Chun-Song YangBryce M Paschal
Dec 17, 2017·Analytical Biochemistry·Jingwen ChenYong Zhang
Jan 19, 2019·ACS Medicinal Chemistry Letters·Rory K MorganMichael S Cohen
Jan 20, 2019·Trends in Immunology·Friedrich A Kunze, Michael O Hottiger
Mar 12, 2019·Journal of the American Chemical Society·Lik Hang YuenRaphael M Franzini
Oct 30, 2019·Nature Chemical Biology·Shuai WangYonghao Yu

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

Related Papers

IDrugs : the Investigational Drugs Journal
J H Li, J Zhang
The Journal of Biological Chemistry
Viatcheslav A SoldatenkovAnatoly Dritschilo
Clinical Advances in Hematology & Oncology : H&O
Ruth Plummer
Journal of Pharmacological and Toxicological Methods
Laura S LubbersIan J Reynolds
© 2021 Meta ULC. All rights reserved