A5018801388- RNA and protein synthesis mechanisms
- DNA Repair Mechanisms
- Malaria Research and Control
- X-ray Diffraction in Crystallography
- CRISPR and Genetic Engineering
- Crystallization and Solubility Studies
- Herpesvirus Infections and Treatments
- Chemical Synthesis and Analysis
- Monoclonal and Polyclonal Antibodies Research
- Poxvirus research and outbreaks
- Advanced biosensing and bioanalysis techniques
- interferon and immune responses
- Computational Drug Discovery Methods
- Alzheimer's disease research and treatments
- RNA Interference and Gene Delivery
- Click Chemistry and Applications
- Genomics and Chromatin Dynamics
- Antimicrobial Peptides and Activities
- Ginkgo biloba and Cashew Applications
- Parkinson's Disease Mechanisms and Treatments
- Photochromic and Fluorescence Chemistry
- Fungal and yeast genetics research
- Synthesis of Indole Derivatives
- Bioactive Compounds and Antitumor Agents
- Venomous Animal Envenomation and Studies
Latvijas Organiskās Sintēzes Institūts
2015-2024
University of Cambridge
2020-2023
2-Aminoquinazolin-4(3H)-ones were identified as a novel class of malaria digestive vacuole plasmepsin inhibitors by using NMR-based fragment screening against Plm II. Initial hit optimization led to submicromolar inhibitor, which was cocrystallized with II produce an X-ray structure the complex. The showed that 2-aminoquinazolin-4(3H)-ones bind open flap conformation enzyme and provided clues target pocket. Further improvement in potency achieved via introduction hydrophobic substituents...
The induction of interferon (IFN)-stimulated genes by STATs is a critical host defense mechanism against virus infection. Here, we report that highly expressed poxvirus protein, 018, inhibits IFN-induced signaling binding to the SH2 domain STAT1, thereby preventing association STAT1 with an activated IFN receptor. Despite encoding other inhibitors signaling, mutant lacking 018 was attenuated in mice. 2.0 Å crystal structure 018:STAT1 complex reveals phosphotyrosine-independent mode STAT1....
Following up the open initiative of anti-malarial drug discovery, a GlaxoSmithKline (GSK) phenotypic screening hit was developed to generate hydroxyethylamine based plasmepsin (Plm) inhibitors exhibiting growth inhibition malaria parasite Plasmodium falciparum at nanomolar concentrations. Lead optimization studies were performed with aim improving Plm selectivity versus related human aspartic protease cathepsin D (Cat D). Optimization using IV as readily accessible model protein, which...
Photoisomerization of diarylethene-modified peptides changes the thermodynamics their binding to MDM2: “closed” photoisomers bind largely due a high negative enthalpy, whereas “open” forms better more favourable entropy.
Significance Despite advances in directed evolution and computational design, engineering of functional proteins remains challenging. Here we demonstrate that rearrangement modular repeats from BRCA2 can yield chimeras with improved interaction properties, while deconstructing the relative energetic contributions different modules across a large interface resolving effects shape complementary or physicochemical properties by empirical observation. This de- reconstruction binding interfaces...
Targeted therapies have increased the treatment options for triple-negative breast cancer patients. However, paucity of targetable biomarkers and tumor heterogeneity limited ability precision-guided interventions to live up their full potential. As affinity-targeting ligands, aptamers show high selectivity toward target molecules. Compared with antibodies, lower molecular weight, stability during transportation, reduced immunogenicity, tissue uptake. Recently, we reported discovery GreenB1...
Alpha-synuclein (α-syn) inclusions in the brain are hallmarks of so-called Lewy body diseases. bodies contain mainly aggregated α-syn together with some other proteins. Monomeric lacks a well-defined three-dimensional structure, but it can aggregate into oligomeric and fibrillar amyloid species, which be detected using specific antibodies. Here we investigate specificity monoclonal MJFR14-6-4-2 We conclude that partial masking epitope unstructured monomer combination high local concentration...
Abstract Intraneuronal α-synuclein inclusions in the brain are hallmarks of so-called Lewy body diseases - Parkinson’s disease and Dementia with bodies. bodies cytoplasmic inclusions, containing mainly aggregated together some other proteins including ubiquitin, neurofilament protein, alpha B crystallin. In its monomeric form, is predominantly localized nerve terminals, regulating neuronal transmission synaptic vesicle trafficking. Monomeric lacks a well-defined three-dimensional structure...
Interaction of BRCA2 through ca. 30 amino acid residue motifs, BRC repeats, with RAD51 is a conserved feature the double-strand DNA break repair by homologous recombination in eukaryotes. In humans binding eight repeats defined two sequence FxxA and LFDE, interacting distinct sites on RAD51. Little known interaction other species, especially protozoans, where variable number are found proteins. Here, we have studied detail interactions Leishmania infantum We show LiBRC1 high-affinity repeat...
An approach for stapled peptide preparation in small scale using recombinant expression of peptide–protein fusions bacteria. We use this to design binders RAD51, characterise their interaction and demonstrate activity cells.
Abstract Exchanges of protein sequence modules support leaps in function unavailable through point mutations during evolution. Here we study the role two RAD51-interacting within eight binding BRC repeats BRCA2. We created 64 chimeric by shuffling these and measured their to RAD51. found that certain shuffled were stronger than any natural repeats, suggesting balancing relative properties repeats. Surprisingly, contribution from was poorly correlated with affinities weak BRC8 repeat...
Summary The induction of interferon-stimulated genes by signal transducer and activator transcription (STAT) proteins, is a critical host defence to fight virus infections. Here, highly expressed poxvirus protein 018 shown inhibit IFN-induced signalling binding the SH2 domain STAT1 prevent association with an activated IFN receptor. Despite presence additional inhibitors signalling, lacking was attenuated in mice. 2.0 Å crystal structure 018:STAT1 complex reveals mechanism for high-affinity,...
Abstract Stapling is a macrocyclisation method that connects amino acid side chains of peptide to improve its pharmacological properties. We describe an approach for stapled preparation and biochemical evaluation combines recombinant expression fusion constructs target peptides cysteine-reactive divinyl-heteroaryl chemistry, as alternative solid-phase synthesis. then employ this workflow prepare evaluate BRC-repeat-derived inhibitors the RAD51 recombinase, showing diverse range secondary...