Publications de Alexander Lund Nielsen

Bulk measurement of membrane permeability for random cyclic peptides in living cells to guide drug development

Christian Heinis, Alexander Lund Nielsen, Anne Sofie Luise Zarda

Cyclic peptides are attractive for drug discovery due to their excellent binding properties and the potential to cross cell membranes. However, by far not all cyclic peptides are cell permeable, and measuring or predicting their membrane permeability is no ...

Wiley2025

Large Macrocyclic Libraries via Thioether Cyclization

Alexander Lund Nielsen

Macrocyclic peptides, known for their high specificity, binding affinity, and potential membrane permeability, represent a promising modality in drug discovery, particularly for intracellular targets deemed undruggable by conventional small molecules. Trad ...

Humana Press Inc.2025

Discovery of De Novo Macrocycle Inhibitors of Histone Deacetylase 11

Christian Heinis, Edward Jeffrey Will, Alexander Lund Nielsen, Anne Sofie Luise Zarda

Histone deacetylase (HDAC) enzymes are epigenetic regulators that affect diverse protein function by removing acyl groups from lysine side chains throughout the proteome. The most recently discovered human isozyme, HDAC11, differs from other HDACs in subst ...

2025

Solid-phase peptide synthesis in 384-well plates

Christian Heinis, Gontran Sangouard, Mischa Schüttel, Sevan Mleh Habeshian, Edward Jeffrey Will, Alexander Lund Nielsen, Anne Sofie Luise Zarda

Newer solid-phase peptide synthesis and release strategies enable the production of short peptides with high purity, allowing direct screening for desired bioactivity without prior chromatographic purification. However, the maximum number of peptides that ...

2024

Cyclic Peptides for Drug Development

Christian Heinis, Xinjian Ji, Alexander Lund Nielsen

Cyclic peptides are fascinating molecules abundantly found in nature and exploited as molecular format for drug development as well as other applications, ranging from research tools to food additives. Advances in peptide technologies made over many years ...

Wiley-VCH Verlag GmbH2024

Large Libraries of Structurally Diverse Macrocycles Suitable for Membrane Permeation

Christian Heinis, Alessandro Angelini, Mischa Schüttel, Ganesh Kumar Mothukuri, Manuel Leonardo Merz, Zsolt Bognár, Xinjian Ji, Edward Jeffrey Will, Alexander Lund Nielsen, Anne Sofie Luise Zarda

Macrocycles offer an attractive format for drug development due to their good binding properties and potential to cross cell membranes. To efficiently identify macrocyclic ligands for new targets, methods for the synthesis and screening of large combinator ...

Wiley-VCH Verlag GmbH2024

Nanomole-scale photochemical thiol-ene chemistry for high-throughput late-stage diversification of peptide macrocycles

Mischa Schüttel, Alexander Lund Nielsen, Mark Daniel Nolan

The photochemical thiol-ene reaction is an efficient method for rapid and chemoselective formation of thioether linkages under mild conditions. It has found widespread use in small-molecule synthesis as well as peptide and protein chemistry. While high-thr ...

WILEY2023

De novo development of small cyclic peptides that are orally bioavailable

Christian Heinis, Manuel Leonardo Merz, Sevan Mleh Habeshian, Xinjian Ji, Alexander Lund Nielsen, Bo Li

Cyclic peptides can bind challenging disease targets with high affinity and specificity, offering enormous opportunities for addressing unmet medical needs. However, as with biological drugs, most cyclic peptides cannot be applied orally because they are r ...

2023

Substrates and Cyclic Peptide Inhibitors of the Oligonucleotide-Activated Sirtuin 7

Alexander Lund Nielsen

The sirtuins are NAD+-dependent lysine deacylases, comprising seven isoforms (SIRT1-7) in humans, which are involved in the regulation of a plethora of biological processes, including gene expression and metabolism. The sirtuins share a common hydrolytic m ...

Wiley-VCH Verlag GmbH2023

Solid-phase peptide synthesis on disulfide-linker resin followed by reductive release affords pure thiol-functionalized peptides

Christian Heinis, Ganesh Kumar Mothukuri, Manuel Leonardo Merz, Zsolt Bognár, Peter Matei Frisius Pânzar, Alexander Lund Nielsen

Thiol groups are suitable handles for site-selectively modifying, immobilizing or cyclizing individual peptides or entire peptide libraries. A limiting step in producing the thiol-functionalized peptides is the chromatographic purification, which is partic ...

2022

Class I histone deacetylases (HDAC1-3) are histone lysine delactylases

Di Zhang, Alexander Lund Nielsen, Carlos Moreno Yruela

Lysine L-lactylation [K(L-la)] is a newly discovered histone mark stimulated under conditions of high glycolysis, such as the Warburg effect. K(L-la) is associated with functions that are different from the widely studied histone acetylation. While K(L-la) ...

2022

Investigation of Carboxylic Acid Isosteres and Prodrugs for Inhibition of the Human SIRT5 Lysine Deacylase Enzyme

Alexander Lund Nielsen

Sirtuin 5 (SIRT5) is a protein lysine deacylase enzyme that regulates diverse biology by hydrolyzing epsilon-N-carboxyacyllysine posttranslational modifications in the cell. Inhibition of SIRT5 has been linked to potential treatment of several cancers but ...

Wiley-VCH Verlag GmbH2022