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Article ; Online: High-throughput screening assay for PARP-HPF1 interaction inhibitors to affect DNA damage repair.

Dhakar, Saurabh S / Galera-Prat, Albert / Lehtiö, Lari

2024 Volume 14, Issue 1, Page(s) 3875

Abstract: ADP-ribosyltransferases PARP1 and PARP2 play a major role in DNA repair mechanism by detecting the DNA damage and inducing poly-ADP-ribosylation dependent chromatin relaxation and recruitment of repair proteins. Catalytic PARP inhibitors are used as ... ...

Abstract	ADP-ribosyltransferases PARP1 and PARP2 play a major role in DNA repair mechanism by detecting the DNA damage and inducing poly-ADP-ribosylation dependent chromatin relaxation and recruitment of repair proteins. Catalytic PARP inhibitors are used as anticancer drugs especially in the case of tumors arising from sensitizing mutations. Recently, a study showed that Histone PARylation Factor (HPF1) forms a joint active site with PARP1/2. The interaction of HPF1 with PARP1/2 alters the modification site from Aspartate/Glutamate to Serine, which has been shown to be a key ADP-ribosylation event in the context of DNA damage. Therefore, disruption of PARP1/2-HPF1 interaction could be an alternative strategy for drug development to block the PARP1/2 activity. In this study, we describe a FRET based high-throughput screening assay to screen inhibitor libraries against PARP-HPF1 interaction. We optimized the conditions for FRET signal and verified the interaction by competing the FRET pair in multiple ways. The assay is robust and easy to automate. Validatory screening showed the robust performance of the assay, and we discovered two compounds Dimethylacrylshikonin and Alkannin, with µM inhibition potency against PARP1/2-HPF1 interaction. The assay will facilitate the discovery of inhibitors against HPF1-PARP1/2 complex and to develop potentially new effective anticancer agents.
MeSH term(s)	Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; DNA Damage ; DNA Repair ; High-Throughput Screening Assays ; Histones/drug effects ; Histones/metabolism ; Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors ; Poly ADP Ribosylation ; Poly(ADP-ribose) Polymerase Inhibitors/chemistry ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
Chemical Substances	Antineoplastic Agents ; Histones ; Poly (ADP-Ribose) Polymerase-1 (EC 2.4.2.30) ; Poly(ADP-ribose) Polymerase Inhibitors ; HPF1 protein, human
Language	English
Publishing date	2024-02-16
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-54123-8
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Protein engineering approach to enhance activity assays of mono-ADP-ribosyltransferases through proximity.

Galera-Prat, Albert / Alaviuhkola, Juho / Alanen, Heli I / Lehtiö, Lari

Protein engineering, design & selection : PEDS

2022 Volume 35

Abstract: Human mono-ADP-ribosylating PARP enzymes have been linked to several clinically relevant processes and many of these PARPs have been suggested as potential drug targets. Despite recent advances in the field, efforts to discover inhibitors have been ... ...

Abstract	Human mono-ADP-ribosylating PARP enzymes have been linked to several clinically relevant processes and many of these PARPs have been suggested as potential drug targets. Despite recent advances in the field, efforts to discover inhibitors have been hindered by the lack of tools to rapidly screen for high potency compounds and profile them against the different enzymes. We engineered mono-ART catalytic fragments to be incorporated into a cellulosome-based octavalent scaffold. Compared to the free enzymes, the scaffold-based system results in an improved activity for the tested PARPs due to improved solubility, stability and the proximity of the catalytic domains, altogether boosting their activity beyond 10-fold in the case of PARP12. This allows us to measure their activity using a homogeneous NAD+ conversion assay, facilitating its automation to lower the assay volume and costs. The approach will enable the discovery of more potent compounds due to increased assay sensitivity.
MeSH term(s)	ADP Ribose Transferases/genetics ; ADP Ribose Transferases/metabolism ; Catalysis ; Humans ; NAD ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Protein Engineering
Chemical Substances	Poly(ADP-ribose) Polymerase Inhibitors ; NAD (0U46U6E8UK) ; ADP Ribose Transferases (EC 2.4.2.-)
Language	English
Publishing date	2022-09-21
Publishing country	England
Document type	Journal Article
ZDB-ID	1466729-0
ISSN	1741-0134 ; 1741-0126
ISSN (online)	1741-0134
ISSN	1741-0126
DOI	10.1093/protein/gzac006
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Article ; Online: Activation of PARP2/ARTD2 by DNA damage induces conformational changes relieving enzyme autoinhibition.

Obaji, Ezeogo / Maksimainen, Mirko M / Galera-Prat, Albert / Lehtiö, Lari

Nature communications

2021 Volume 12, Issue 1, Page(s) 3479

Abstract: Human PARP2/ARTD2 is an ADP-ribosyltransferase which, when activated by 5'-phosphorylated DNA ends, catalyses poly-ADP-ribosylation of itself, other proteins and DNA. In this study, a crystal structure of PARP2 in complex with an activating 5'- ... ...

Abstract	Human PARP2/ARTD2 is an ADP-ribosyltransferase which, when activated by 5'-phosphorylated DNA ends, catalyses poly-ADP-ribosylation of itself, other proteins and DNA. In this study, a crystal structure of PARP2 in complex with an activating 5'-phosphorylated DNA shows that the WGR domain bridges the dsDNA gap and joins the DNA ends. This DNA binding results in major conformational changes, including reorganization of helical fragments, in the PARP2 regulatory domain. A comparison of PARP1 and PARP2 crystal structures reveals how binding to a DNA damage site leads to formation of a catalytically competent conformation. In this conformation, PARP2 is capable of binding substrate NAD
MeSH term(s)	Carrier Proteins/metabolism ; DNA/chemistry ; DNA/metabolism ; DNA Breaks, Double-Stranded ; DNA Damage ; DNA Repair ; Enzyme Activation ; Humans ; NAD/metabolism ; Nuclear Proteins/metabolism ; Phosphorylation ; Poly (ADP-Ribose) Polymerase-1/chemistry ; Poly (ADP-Ribose) Polymerase-1/metabolism ; Poly ADP Ribosylation ; Poly(ADP-ribose) Polymerases/chemistry ; Poly(ADP-ribose) Polymerases/metabolism ; Protein Binding ; Protein Conformation ; Protein Domains ; Protein Unfolding
Chemical Substances	Carrier Proteins ; HPF1 protein, human ; Nuclear Proteins ; NAD (0U46U6E8UK) ; DNA (9007-49-2) ; PARP1 protein, human (EC 2.4.2.30) ; PARP2 protein, human (EC 2.4.2.30) ; Poly (ADP-Ribose) Polymerase-1 (EC 2.4.2.30) ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30)
Language	English
Publishing date	2021-06-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-23800-x
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Article ; Online: An Evolutionary Perspective on the Origin, Conservation and Binding Partner Acquisition of Tankyrases.

Sowa, Sven T / Bosetti, Chiara / Galera-Prat, Albert / Johnson, Mark S / Lehtiö, Lari

Biomolecules

2022 Volume 12, Issue 11

Abstract: Tankyrases are poly-ADP-ribosyltransferases that regulate many crucial and diverse cellular processes in humans such as Wnt signaling, telomere homeostasis, mitotic spindle formation and glucose metabolism. While tankyrases are present in most animals, ... ...

Abstract	Tankyrases are poly-ADP-ribosyltransferases that regulate many crucial and diverse cellular processes in humans such as Wnt signaling, telomere homeostasis, mitotic spindle formation and glucose metabolism. While tankyrases are present in most animals, functional differences across species may exist. In this work, we confirm the widespread distribution of tankyrases throughout the branches of multicellular animal life and identify the single-celled choanoflagellates as earliest origin of tankyrases. We further show that the sequences and structural aspects of TNKSs are well-conserved even between distantly related species. We also experimentally characterized an anciently diverged tankyrase homolog from the sponge
MeSH term(s)	Humans ; Animals ; Tankyrases/genetics ; Tankyrases/chemistry ; Tankyrases/metabolism ; Telomere Homeostasis ; Wnt Signaling Pathway
Chemical Substances	Tankyrases (EC 2.4.2.30)
Language	English
Publishing date	2022-11-15
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom12111688
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Article ; Online: Discovery of 2-Amide-3-methylester Thiophenes that Target SARS-CoV-2 Mac1 and Repress Coronavirus Replication, Validating Mac1 as an Antiviral Target.

Wazir, Sarah / Parviainen, Tomi A O / Pfannenstiel, Jessica J / Duong, Men Thi Hoai / Cluff, Daniel / Sowa, Sven T / Galera-Prat, Albert / Ferraris, Dana / Maksimainen, Mirko M / Fehr, Anthony R / Heiskanen, Juha P / Lehtiö, Lari

Journal of medicinal chemistry

2024 Volume 67, Issue 8, Page(s) 6519–6536

Abstract: The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has made it clear that further development of antiviral therapies will be needed. Here, we describe small-molecule inhibitors for SARS-CoV-2 Mac1, which ... ...

Abstract	The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has made it clear that further development of antiviral therapies will be needed. Here, we describe small-molecule inhibitors for SARS-CoV-2 Mac1, which counters ADP-ribosylation-mediated innate immune responses. Three high-throughput screening hits had the same 2-amide-3-methylester thiophene scaffold. We studied the compound binding mode using X-ray crystallography, allowing us to design analogues. Compound
MeSH term(s)	Antiviral Agents/pharmacology ; Antiviral Agents/chemistry ; Antiviral Agents/chemical synthesis ; Thiophenes/pharmacology ; Thiophenes/chemistry ; Thiophenes/chemical synthesis ; Virus Replication/drug effects ; Humans ; SARS-CoV-2/drug effects ; Animals ; Drug Discovery ; Mice ; Crystallography, X-Ray ; COVID-19 Drug Treatment ; Structure-Activity Relationship ; Murine hepatitis virus/drug effects
Chemical Substances	Antiviral Agents ; Thiophenes
Language	English
Publishing date	2024-04-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.3c02451
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Zs.B 151: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Activation of PARP2/ARTD2 by DNA damage induces conformational changes relieving enzyme autoinhibition

Ezeogo Obaji / Mirko M. Maksimainen / Albert Galera-Prat / Lari Lehtiö

Nature Communications, Vol 12, Iss 1, Pp 1-

2021 Volume 8

Abstract: Poly(ADP-ribose) polymerase 2 (PARP2) is activated by 5′-phosphorylated DNA breaks but the molecular mechanism is not fully understood. Here, the authors report a crystal structure of PARP2 bound to an activating DNA fragment, providing insights into the ...

Abstract	Poly(ADP-ribose) polymerase 2 (PARP2) is activated by 5′-phosphorylated DNA breaks but the molecular mechanism is not fully understood. Here, the authors report a crystal structure of PARP2 bound to an activating DNA fragment, providing insights into the structural changes that lead to PARP2 activation.
Keywords	Science ; Q
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Preparation of screening assays for ADP-ribosyl readers and erasers using the GAP-tag as a binding probe.

Sowa, Sven T / Galera-Prat, Albert / Wazir, Sarah / Alanen, Heli I / Maksimainen, Mirko M / Lehtiö, Lari

STAR protocols

2022 Volume 3, Issue 1, Page(s) 101147

Abstract: Here, we describe a protocol to set up a screening assay for ADP-ribosyl binding proteins including proteins that possess O-glycosidase or N-glycosidase activities. The FRET-based assay measures the interaction of any ADP-ribosyl binding protein fused to ...

Abstract	Here, we describe a protocol to set up a screening assay for ADP-ribosyl binding proteins including proteins that possess O-glycosidase or N-glycosidase activities. The FRET-based assay measures the interaction of any ADP-ribosyl binding protein fused to CFP with a cysteine-ADP-ribosylated GAP-tag fused to YFP. Recombinant PtxS1 and PARP2 are used to mono-ADP-ribosylate and poly-ADP-ribosylate the GAP-tag. The protocol does not require specialized compounds or substrates, making it accessible and easy to adapt in any laboratory or for other proteins of interest. For complete details on the use and execution of this profile, please refer to Sowa et al. (2021).
MeSH term(s)	Adenosine Diphosphate ; Biological Assay ; Glycoside Hydrolases ; Proteins
Chemical Substances	Proteins ; Adenosine Diphosphate (61D2G4IYVH) ; Glycoside Hydrolases (EC 3.2.1.-)
Language	English
Publishing date	2022-01-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2666-1667
ISSN (online)	2666-1667
DOI	10.1016/j.xpro.2022.101147
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Synthetically accessible de novo design using reaction vectors: Application to PARP1 inhibitors.

Ghiandoni, Gian Marco / Flanagan, Stuart R / Bodkin, Michael J / Nizi, Maria Giulia / Galera-Prat, Albert / Brai, Annalaura / Chen, Beining / Wallace, James E A / Hristozov, Dimitar / Webster, James / Manfroni, Giuseppe / Lehtiö, Lari / Tabarrini, Oriana / Gillet, Valerie J

Molecular informatics

2024 Volume 43, Issue 4, Page(s) e202300183

Abstract: De novo design has been a hotly pursued topic for many years. Most recent developments have involved the use of deep learning methods for generative molecular design. Despite increasing levels of algorithmic sophistication, the design of molecules that ... ...

Abstract	De novo design has been a hotly pursued topic for many years. Most recent developments have involved the use of deep learning methods for generative molecular design. Despite increasing levels of algorithmic sophistication, the design of molecules that are synthetically accessible remains a major challenge. Reaction-based de novo design takes a conceptually simpler approach and aims to address synthesisability directly by mimicking synthetic chemistry and driving structural transformations by known reactions that are applied in a stepwise manner. However, the use of a small number of hand-coded transformations restricts the chemical space that can be accessed and there are few examples in the literature where molecules and their synthetic routes have been designed and executed successfully. Here we describe the application of reaction-based de novo design to the design of synthetically accessible and biologically active compounds as proof-of-concept of our reaction vector-based software. Reaction vectors are derived automatically from known reactions and allow access to a wide region of synthetically accessible chemical space. The design was aimed at producing molecules that are active against PARP1 and which have improved brain penetration properties compared to existing PARP1 inhibitors. We synthesised a selection of the designed molecules according to the provided synthetic routes and tested them experimentally. The results demonstrate that reaction vectors can be applied to the design of novel molecules of biological relevance that are also synthetically accessible.
MeSH term(s)	Poly(ADP-ribose) Polymerase Inhibitors/chemistry ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors/chemical synthesis ; Drug Design ; Humans ; Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors ; Poly (ADP-Ribose) Polymerase-1/metabolism ; Software
Chemical Substances	Poly(ADP-ribose) Polymerase Inhibitors ; Poly (ADP-Ribose) Polymerase-1 (EC 2.4.2.30) ; PARP1 protein, human (EC 2.4.2.30)
Language	English
Publishing date	2024-02-06
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2537668-8
ISSN	1868-1751 ; 1868-1743
ISSN (online)	1868-1751
ISSN	1868-1743
DOI	10.1002/minf.202300183
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Article: Discovery of 2-amide-3-methylester thiophenes that target SARS-CoV-2 Mac1 and repress coronavirus replication, validating Mac1 as an anti-viral target.

bioRxiv : the preprint server for biology

2023

Abstract: The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has made it clear that further development of antiviral therapies will be needed to combat additional SARS-CoV-2 variants or novel CoVs. Here, we describe ... ...

Abstract	The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has made it clear that further development of antiviral therapies will be needed to combat additional SARS-CoV-2 variants or novel CoVs. Here, we describe small molecule inhibitors for SARS-CoV-2 Mac1, which counters ADP-ribosylation mediated innate immune responses. The compounds inhibiting Mac1 were discovered through high-throughput screening (HTS) using a protein FRET-based competition assay and the best hit compound had an IC
Language	English
Publishing date	2023-12-27
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.28.555062
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Activity-Based Screening Assay for Mono-ADP-Ribosylhydrolases.

Wazir, Sarah / Maksimainen, Mirko M / Alanen, Heli I / Galera-Prat, Albert / Lehtiö, Lari

SLAS discovery : advancing life sciences R & D

2020 Volume 26, Issue 1, Page(s) 67–76

Abstract: ADP-ribosylation is a post-translational modification involved in the regulation of many vital cellular processes. This posttranslational modification is carried out by ADP-ribosyltransferases converting β- ... ...

Abstract	ADP-ribosylation is a post-translational modification involved in the regulation of many vital cellular processes. This posttranslational modification is carried out by ADP-ribosyltransferases converting β-NAD
MeSH term(s)	ADP-Ribosylation ; Biological Assay/methods ; Carboxylic Ester Hydrolases/chemistry ; Carboxylic Ester Hydrolases/metabolism ; Enzyme Activation ; Humans ; NAD/metabolism ; Protein Processing, Post-Translational
Chemical Substances	NAD (0U46U6E8UK) ; Carboxylic Ester Hydrolases (EC 3.1.1.-) ; MACROD1 protein, human (EC 3.1.1.-)
Language	English
Publishing date	2020-06-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2885123-7
ISSN	2472-5560 ; 2472-5552
ISSN (online)	2472-5560
ISSN	2472-5552
DOI	10.1177/2472555220928911
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