A5044367093- HIV Research and Treatment
- Neuroscience and Neuropharmacology Research
- HIV/AIDS drug development and treatment
- Enzyme Structure and Function
- Protein Kinase Regulation and GTPase Signaling
- Cytomegalovirus and herpesvirus research
- Genomics, phytochemicals, and oxidative stress
- Ubiquitin and proteasome pathways
- Immune Response and Inflammation
- Signaling Pathways in Disease
- T-cell and B-cell Immunology
- Influenza Virus Research Studies
- Periodontal Regeneration and Treatments
- interferon and immune responses
- Plant Stress Responses and Tolerance
- Wound Healing and Treatments
- Computational Drug Discovery Methods
- RNA and protein synthesis mechanisms
- Hepatitis C virus research
- Hepatitis B Virus Studies
- Chemical Synthesis and Analysis
- Glycosylation and Glycoproteins Research
- Glutathione Transferases and Polymorphisms
- Monoclonal and Polyclonal Antibodies Research
- Galectins and Cancer Biology
University of Copenhagen
2019-2025
Uppsala University
2017-2020
University of Bergen
2010-2014
Inhibiting the protein–protein interaction (PPI) between transcription factor Nrf2 and its repressor protein Keap1 has emerged as a promising strategy to target oxidative stress in diseases, including central nervous system (CNS) disorders. Numerous non-covalent small-molecule Keap1−Nrf2 PPI inhibitors have been reported date, but many feature suboptimal physicochemical properties for permeating blood–brain barrier, while others contain problematic structural moieties. Here, we present first...
Polyubiquitin chains are flexible multidomain proteins, whose conformational dynamics enable them to regulate multiple biological pathways. Their dynamic is determined by the linkage between ubiquitins and number of ubiquitin units. Characterizing polyubiquitin behavior as a function their length hampered because increasing system size variability. Here, we introduce new approach efficiently integrating small-angle x-ray scattering with simulations allowing us accurately characterize linear...
Targeting the protein–protein interaction (PPI) between nuclear factor erythroid 2-related 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1–Nrf2 PPI inhibitors were dissected into 77 fragments in fragment-based deconstruction reconstruction (FBDR) study tested four orthogonal assays. This gave 17 fragment hits which shown by X-ray crystallography bind...
Significance GHB is a natural brain metabolite of GABA, previously reported to be neuroprotective. However, the high-affinity binding site for has remained elusive almost 40 y. We here unveil CaMKIIα, highly important neuronal kinase, as long-sought-after target. Via specific interaction within central hub domain analogs act stabilize oligomer complex. This potentially explains pronounced neuroprotective effects in cultured neurons exposed chemical insult and mice ischemia. The postischemic...
Targeting the protein–protein interaction (PPI) between transcription factor nuclear erythroid 2-related 2 (Nrf2) and its repressor, Kelch-like ECH-associated protein 1 (Keap1), constitutes a promising strategy for treating diseases involving oxidative stress inflammation. Here, fragment-based drug discovery (FBDD) campaign resulted in novel, high-affinity (Ki = 280 nM), cell-active noncovalent small-molecule Keap1-Nrf2 PPI inhibitors. We screened 2500 fragments using orthogonal...
The Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) plays a crucial role in regulating neuronal signaling and higher brain functions, being involved various diseases. Utilization of small molecules targeting the CaMKIIα hub domain has proved to be promising strategy for specific modulation future therapy. Through an silico structure-based virtual screening campaign, we herein identified 2-arylthiazole-4-carboxylic acids as new class high-affinity ligands. Particularly,...
Nicotinamide adenine dinucleotide phosphate oxidase isoform 2 is an enzyme complex, which generates reactive oxygen species and contributes to oxidative stress. The p47phox–p22phox interaction critical for the activation of catalytical NOX2 domain, p47phox a potential target therapeutic intervention. By screening 2500 fragments using fluorescence polarization thermal shift assay validation by surface plasmon resonance, we found eight hits toward tandem SH3 domain (p47phoxSH3A–B) with KD...
The multifunctional protein kinase pUL97 of human cytomegalovirus (HCMV) strongly determines the efficiency virus replication. Previously, existence two isoforms that arise from alternative translational initiation and show a predominant nuclear localization was described. Two bipartite sequences, NLS1 NLS2, were identified in N terminus large isoform, whilst small isoform exclusively contained NLS2. current study found following: (i) HCMV-infected primary fibroblasts showed accumulations...
Abstract The full length human histone 3 lysine 4 demethylase KDM5B (PLU-1/Jarid1B) has been studied using Hydrogen/Deuterium exchange mass spectrometry, homology modelling, sequence analysis, small angle X-ray scattering and electron microscopy. This first structure on an intact multi-domain Jumonji reveal that the so-called PLU region, in central region of KDM5B, a curved α-helical three-dimensional structure, acts as rigid linker between catalytic core comprising four α-helices, loop PHD2...
Abstract γ‐Hydroxybutyric acid (GHB) analogs are small molecules that bind competitively to a specific cavity in the oligomeric CaMKIIα hub domain. Binding affects conformation and stability of domain, which may explain neuroprotective action some these compounds. Here, we describe molecular details interaction larger‐type GHB analog 2‐(6‐(4‐chlorophenyl)imidazo[1,2‐b]pyridazine‐2‐yl)acetic (PIPA). Like smaller‐type analogs, PIPA binding domain promoted thermal stability. additionally...
Abstract Background The HIV-1 p6 Gag protein regulates the final abscission step of nascent virions from cell membrane by action two late assembly (L-) domains. Although is located within one most polymorphic regions gag gene, 52 amino acid peptide binds at least to cellular budding factors (Tsg101 and ALIX), a substrate for phosphorylation, ubiquitination, sumoylation, mediates incorporation accessory Vpr into viral particles. As expected, known functional domains mostly overlap with...
Direct acting antivirals (DAAs) provide efficient hepatitis C virus (HCV) therapy and clearance for a majority of patients, but are not available or effective all patients. They risk developing HCV-induced hepatocellular carcinoma (HCC), which the mechanism remains obscure is missing. Annexin A2 (AnxA2) has been reported to co-precipitate with non-structural (NS) HCV proteins NS5B NS3/NS4A, indicating role in HCC tumorigenesis effect on DAA therapy.Surface plasmon resonance biosensor...
Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIα) is a brain-relevant and an emerging drug target for ischemic stroke neurodegenerative disorders. Despite reported CaMKIIα inhibitors, their usefulness limited by low subtype selectivity brain permeability. (E)-2-(5-Hydroxy-5,7,8,9-tetrahydro-6H-benzo[7]annulen-6-ylidene)acetic acid (NCS-382) structurally related to the proposed neuromodulator, γ-hydroxybutyric acid, brain-penetrating high nanomolar-affinity ligand selective hub...
Abstract Class-switching to IgG2a/c in mice is a hallmark response intracellular pathogens. T cells can promote class-switching and the predominant pathway for induction of antibody responses has been suggested be via stimulation from Th1 cells. We previously formulated CAF®01 (cationic liposomes containing dimethyldioctadecylammonium bromide (DDA) Trehalose-6,6-dibehenate (TDB)) with lipidated TLR7/8 agonist 3M-052 (DDA/TDB/3M-052), which promoted robust immunity newborn mice. When testing...
Cyclophilin A (CypA) represents a potential target for antiretroviral therapy since inhibition of CypA suppresses human immunodeficiency virus type 1 (HIV-1) replication, although the mechanism through which modulates HIV-1 infectivity still remains unclear. The interaction viral protein R (Vpr) with peptidyl prolyl isomerase is known to occur in vitro and vivo. However, nature Pro-35 N-terminal Vpr has remained undefined.Characterization interactions peptides been achieved using combination...
Cyclophilin A (CypA) represents a potential key molecule in future antiretroviral therapy since inhibition of CypA suppresses human immunodeficiency virus type 1 (HIV-1) replication. interacts with the proteins Capsid (CA) and Vpr, however, mechanism through which influences HIV-1 infectivity still remains unclear.Here interaction full-length Vpr host cellular factor has been characterized quantified by surface plasmon resonance spectroscopy. C-terminal region comprising 16 residues...
Fibrin is an essential constituent of the coagulation cascade, and formation hemostatic fibrin clots central to wound healing. are over time degraded into degradation products as injured tissue replaced by granulation tissue. Our goal was study role product fragment E (FnE) in fibroblast activation migration. We present evidence that FnE a chemoattractant for fibroblasts can potentiate TGF-β-induced myofibroblast formation. forms stable complex with αVβ3 integrin, integrin β3 subunit...
The Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) is a brain-relevant involved in long-term potentiation and synaptic plasticity. We have recently pinpointed the CaMKIIα hub domain as long-sought-after high-affinity target of γ-hydroxybutyrate ligands substantiated with high-resolution cocrystal 5-hydroxydiclofenac (3). Herein, we employed silico approaches to rationalize guide synthesis pharmacological characterization new series analogues circumventing chemical stability problems...
The interaction between the Staphylococcal Protein A (SpA) domain B (the basis of Affibody) molecule and Fc IgG is key to use Affibodies in affinity chromatography potential therapies against certain inflammatory diseases. Despite its importance four-decade history, our knowledge this has never been matured. We elucidate reasons why single-substitutions SpA which improve may be very rare, also discover substitutions potentially serve several engineering purposes. used a variation FoldX...
Allosteric inhibitors of hepatitis C virus (HCV) non-structural protein 5B (NS5B) polymerase are effective for treatment genotype 1, although their mode action and potential to inhibit other isolates genotypes not well established. We have used biophysical techniques a novel biosensor-based real-time assay investigate the mode-of-action selectivity four against enzyme from 1b (BK Con1) 3a. Two thumb (lomibuvir filibuvir) interacted with all three NS5B variants, affinities 3a were low. Of two...
The HIV-1 p6 Gag protein contains two late assembly (l-) domains that recruit proteins of the endosomal sorting complex required for transport (ESCRT) pathway to mediate membrane fission between nascent virion and cell membrane. It was recently demonstrated mutation highly conserved Ser-40 Phe (S40F) disturbs CA-SP1 processing, virus morphogenesis, infectivity. also causes formation filopodia-like structures, while release remains unaffected. Here, we show S40F, but not conservative Asp...