A5055954638- Sirtuins and Resveratrol in Medicine
- DNA and Nucleic Acid Chemistry
- Advanced biosensing and bioanalysis techniques
- Histone Deacetylase Inhibitors Research
- RNA Interference and Gene Delivery
- Peptidase Inhibition and Analysis
- Autophagy in Disease and Therapy
- Protein Degradation and Inhibitors
- Calcium signaling and nucleotide metabolism
- Biochemical and Molecular Research
- Click Chemistry and Applications
- Cancer, Hypoxia, and Metabolism
- Biochemical effects in animals
- RNA and protein synthesis mechanisms
- Adenosine and Purinergic Signaling
- Tea Polyphenols and Effects
- Synthesis and Catalytic Reactions
- Signaling Pathways in Disease
- Chemical Synthesis and Analysis
- Adipose Tissue and Metabolism
- Carbohydrate Chemistry and Synthesis
- Cancer Treatment and Pharmacology
- Biopolymer Synthesis and Applications
- HIV/AIDS drug development and treatment
- Enzyme Structure and Function
University of Copenhagen
2015-2021
Novo Nordisk (Denmark)
2019
Technical University of Denmark
2012-2016
Danish Geotechnical Society
2014
Institute of Organic Chemistry
2014
University of Southern Denmark
2006-2013
Swedish Chemicals Agency
2012
Danish National Research Foundation
2010
Karolinska Institutet
2010
Iuliu Hațieganu University of Medicine and Pharmacy
2010
Systematic screening of the activities eleven human zinc-dependent lysine deacylases against a series fluorogenic substrates (see scheme) as well kinetic evaluation revealed for screenings histone deacetylases HDAC10 and HDAC11 at reasonably low enzyme concentrations. Furthermore, HDAC3 in complex with nuclear receptor corepressor 1 (HDAC3–NCoR1) was shown to harbor decrotonylase activity vitro.
Protein lysine posttranslational modification by an increasing number of different acyl groups is becoming appreciated as a regulatory mechanism in cellular biology. Sirtuins are class III histone deacylases that use NAD+ co-substrate during amide bond hydrolysis. Several studies have described the sirtuins sensors NAD+/NADH ratio, but it has not been formally tested for all mammalian vitro. To address this problem, we first synthesized wide variety peptide-based probes, which were used to...
The sirtuin enzymes are important regulatory deacylases in a variety of biochemical contexts and may therefore be potential therapeutic targets through either activation or inhibition by small molecules. Here, we describe the discovery most potent inhibitor 5 (SIRT5) reported to date. We provide rationalization mode binding solving co-crystal structures selected inhibitors complex with both human zebrafish SIRT5, which insight for future optimization more "drug-like" properties. Importantly,...
Sirtuin 2 (SIRT2) is a protein deacylase enzyme that removes acetyl groups and longer chain acyl from post-translationally modified lysine residues. Here, we developed small peptide-based inhibitors of its activity in living cells culture.
The class III lysine deacylases (KDACs), also known as the sirtuins, have emerged interesting drug targets for therapeutic intervention in a variety of diseases. To gain deeper understanding processes affected by development selective small molecule modulators individual isozymes has been longstanding goal. Essential discovery novel modulators, however, are good screening protocols and mechanistic insights with regard to question. We therefore evaluated activities seven human sirtuin...
Abstract Histone deacetylases (HDACs) have the ability to cleave acetyl groups of ε ‐ N ‐acetylated lysine residues in a variety proteins. Given that human cells contain thousands different acetylated residues, HDACS may regulate wide processes including some implicated conditions such as cancer and neurodegenerative disorders. Herein we report synthesis vitro biochemical profiling series compounds, known inhibitors well novel chemotypes, incorporate putative new zinc binding domains. By...
Sirtuins are important regulators of lysine acylation, which is implicated in cellular metabolism and transcriptional control. This makes the sirtuin class enzymes interesting targets for development small molecule probes with pharmaceutical potential. To achieve detailed profiling kinetic insight regarding inhibitors, it to have access efficient assays. In this work, we report readily synthesized fluorogenic substrates enabling enzyme-economical evaluation SIRT2 inhibitors a continuous...
Herein we describe the reversible changing of DNA duplex thermal stability by exploiting transition metal complexation phenomena. A terpyridine ligand was conjugated to N2'-atoms 2'-amino-2'-deoxyuridine and its locked counterpart 2'-amino-LNA, these metal-complexing monomers were incorporated into oligodeoxyribonucleotides. Upon addition varying amounts ions, duplexes containing terpyridine-functionalized units in different constitutions affected degrees (ΔTm values = −15.5 +49.0 °C,...
Histone deacetylases (HDACs) are validated targets for treatment of certain cancer types and play numerous regulatory roles in biology, ranging from epigenetics to metabolism. Small molecules highly important as tool compounds probing these mechanisms well the development new medicines. Therefore, detailed mechanistic information precise characterization chemical probes used investigate effects HDAC enzymes vital. We interrogated Nature's arsenal macrocyclic nonribosomal peptide inhibitors...
Chemically modified oligonucleotides are increasingly applied in nucleic acid based therapeutics and diagnostics. LNA (locked acid) its diastereomer α-L-LNA two promising examples thereof that exhibit increased thermal enzymatic stability. Herein, the synthesis, biophysical characterization, molecular modeling of N2′-functionalized 2′-amino-α-L-LNA is described. Chemoselective N2′-functionalization protected amino alcohol 1 followed by phosphitylation afforded a structurally varied set...
Thymin-1-yl-acetic acid and adenin-9-yl-acetic have been coupled to the N2′-atom of a 2′-amino-LNA thymine nucleoside, these "double-headed" LNA monomers incorporated into oligodeoxyribonucleotides via their corresponding phosphoramidite derivatives. Oligonucleotides containing modified nucleotides show in most cases increased thermal stability when forming duplexes with complementary DNA, even allowing multiple incorporations. Incorporation both strands also led stable duplexes, however, no...
Oligonucleotides (ONs) modified with a 2′-N-(pyren-1-yl)acetyl-2′-amino-α-L-LNA thymine monomer Y flanked on the 3′-side by an abasic site Φ (i.e., YΦ-unit) exhibit unprecedented increases in thermal affinity (ΔTm values) toward target strands containing sites per YΦ unit >+33.0 °C 9-mer duplexes relative to unmodified ONs). Biophysical studies along force field calculations suggest that conformationally locked 2-oxo-5-azabicyclo[2.2.1]heptane skeleton of Y, concert short rigid acetyl...
The development of synthetic agents that recognize double-stranded DNA (dsDNA) is a long-standing goal inspired by the promise for tools detect, regulate, and modify genes. Progress has been made with triplex-forming oligonucleotides, peptide nucleic acids, polyamides, but substantial efforts are currently devoted to alternative strategies overcome limitations observed classic approaches. In 2005, we introduced Invader locked acids (LNAs), i.e., probes activated mixed-sequence recognition...
Kinetic evaluation of HDAC inhibitors containing different zinc-binding chemotypes demonstrates that trifluoromethyl ketone-containing compounds can inhibit individual isozymes <italic>via</italic> differential mechanisms.
Sirtuin 3 (SIRT3) is the major protein lysine deacetylase in mitochondria. This hydrolase regulates a wide range of metabolically involved enzymes and has been considered as potential drug target certain cancers. Investigation pharmacological intervention challenging due to lack potent selective inhibitors SIRT3. Here, we developed strategy for inhibition SIRT3 cells, over its structurally similar isozymes that localize primarily nucleus (SIRT1) cytosol (SIRT2). was achieved by directing...
A convergent route to a new class of locked nucleic acids, i.e., 2'-amino-α-L-LNA, has been developed. The optimized synthetic the corresponding phosphoramidite building block thymine proceeds in 4% overall yield over 15 steps from starting diol. Crucial include (a) introduction C2-azido group prior nucleobase coupling, (b) Vorbrüggen glycosylation primarily affording desired α-anomer, (c) separation α-l-ribo- and β-l-ribo-configured bicyclic nucleosides, (d) selection suitable protecting...
Zorro-LNA (Zorro) is a newly developed, oligonucleotide (ON)-based, Z-shaped construct with the potential of specific binding to each strand duplex DNA. The first-generation Zorros are formed by two hybridized LNA/DNA mixmers (2-ON Zorros) and was hypothesized invade. We have now established method, which conclusively demonstrates that an LNA ON can invade into To make smaller in size easier design, we synthesized 3′–5′–5′–3′ single-stranded (ssZorro) using both 3′- 5′-phosphoramidites. With...
Energetically activated double-stranded probes with interstrand arrangements of intercalator-functionalized nucleotides enable recognition mixed-sequence DNA single nucleotide fidelity.