A5045481715- DNA and Nucleic Acid Chemistry
- Advanced biosensing and bioanalysis techniques
- RNA Interference and Gene Delivery
- Chemical Synthesis and Analysis
- Alzheimer's disease research and treatments
- Click Chemistry and Applications
- Parkinson's Disease Mechanisms and Treatments
- Synthesis and Characterization of Heterocyclic Compounds
- Synthesis and Catalytic Reactions
- Bacterial biofilms and quorum sensing
- Synthesis and Biological Evaluation
- Bacteriophages and microbial interactions
- RNA and protein synthesis mechanisms
- Chemical Reaction Mechanisms
- Phenothiazines and Benzothiazines Synthesis and Activities
- Synthesis of heterocyclic compounds
- Cancer therapeutics and mechanisms
- Synthesis and biological activity
- Luminescence and Fluorescent Materials
- Oxidative Organic Chemistry Reactions
- Antibiotic Resistance in Bacteria
- Bacterial Genetics and Biotechnology
- Catalytic C–H Functionalization Methods
- Molecular Sensors and Ion Detection
- Chemical synthesis and alkaloids
Umeå University
2016-2025
Washington University in St. Louis
2012-2019
Curli are extracellular functional amyloids that assembled by enteric bacteria during biofilm formation and host colonization. An efficient secretion system chaperone network ensures the major curli fiber subunit, CsgA, does not form intracellular amyloid aggregates. We discovered periplasmic protein CsgC was a highly effective inhibitor of CsgA formation. In absence CsgC, formed toxic vitro, inhibited at substoichiometric concentrations maintained in non-β-sheet-rich conformation....
Herein, we describe the X-ray structure-based design and optimization of biaryl mannoside FimH inhibitors. Diverse modifications to ring improve druglike physical pharmacokinetic properties mannosides were assessed for binding affinity based on their effects hemagglutination biofilm formation along with direct assays. Substitution phenyl ortho glycosidic bond results in large potency enhancements several-fold higher than those corresponding unsubstituted matched pairs can be rationalized...
Abstract The insulin-degrading enzyme (IDE) degrades amyloidogenic proteins such as Amyloid β (Αβ) and Islet Polypeptide (IAPP), i.e. peptides associated with Alzheimer’s disease type 2 diabetes, respectively. In addition to the protease activity normally IDE function an additional involving formation of stable, irreversible complexes both Αβ α-synuclein, protein involved in Parkinson’s disease, was recently proposed. Here, we have investigated functional consequences IDE-α-synuclein...
Abstract Mitochondrial DNA (mtDNA) replication stalling is considered an initial step in the formation of mtDNA deletions that associate with genetic inherited disorders and aging. However, molecular details how stalled forks lead to accumulation are still unclear. deletion breakpoints preferentially occur at sequence motifs predicted form G-quadruplexes (G4s), four-stranded nucleic acid structures can fold guanine-rich regions. Whether G4s vivo their potential implication for instability...
G-quadruplex (G4) DNA structures are prevalent secondary implicated in fundamental cellular functions, such as replication and transcription. Furthermore, G4 directly correlated to human diseases cancer have been highlighted promising therapeutic targets for their ability regulate disease-causing genes, e.g., oncogenes. Small molecules that bind stabilize these thus valuable from a perspective helpful studying the biological functions of structures. However, there hundreds thousands motifs...
Non-canonical G-quadruplex (G4) DNA structures play key roles in cellular regulation and are promising targets for cancer therapy. This study reports the design, synthesis, biophysical evaluation of 15 novel pyridine bis-quinazoline derivatives their ability to selectively bind stabilize G4 structures. The pyridine-bis-quinazoline central fragment was synthesized with various amine side chains via a 4-5 step sequence high yields. Comprehensive analyses using different fluorescence resonance...
Small organic molecules that inhibit functional bacterial amyloid fibers, curli, are promising new antibiotics. Here we investigated the mechanism by which ring-fused 2-pyridone FN075 inhibits fibrillation of curli protein CsgA. Using a variety biophysical techniques, found promotes CsgA to form off-pathway, non-amyloidogenic oligomeric species. In light generic properties amyloids, tested whether would also affect reaction human α-synuclein, an amyloid-forming involved in Parkinson's...
Pilicides block pili formation by binding to pilus chaperones and blocking their function in the chaperone/usher pathway E. coli. Various C-2 substituents were introduced on pilicide scaffold design synthetic method developments. Experimental evaluation showed that proper substitution of this position affected biological activity compound. Aryl resulted pilicides with significantly increased potencies as measured pili-dependent biofilm hemagglutination assays. The structural basis PapD...
Amyloid formation is historically associated with cytotoxicity, but many organisms produce functional amyloid fibers (e.g., curli) as a normal part of cell biology. Two E. coli genes in the curli operon encode chaperone-like proteins CsgC and CsgE that both can reduce vitro by CsgA. was also found to arrest human amyloidogenic protein α-synuclein, which involved Parkinson's disease. Here, we report inhibitory effects arise due transient interactions promote spherical α-synuclein oligomers....
ABSTRACT Chaperone-usher pathway (CUP) pili are extracellular organelles produced by Gram-negative bacteria that mediate bacterial pathogenesis. Small-molecule inhibitors of CUP pili, termed pilicides, were rationally designed and shown to inhibit type 1 or P piliation. Here, we show pilicide ec240 decreased the levels 1, P, S Transcriptomic proteomic analyses using cystitis isolate UTI89 revealed dysregulated motility. Paradoxically, transcript pilus genes increased during growth in ec240,...
The signal transducer and activator of transcription 3 (STAT3) protein is a master regulator most key hallmarks enablers cancer, including cell proliferation the response to DNA damage. G-Quadruplex (G4) structures are four-stranded noncanonical enriched at telomeres oncogenes' promoters. In cancer cells, stabilization G4 DNAs leads replication stress damage accumulation therefore considered promising target for oncotherapy. Here, we designed synthesized novel quinazoline-based compounds...
The design of turn-on dyes with optical signals sensitive to the formation supramolecular structures provides fascinating and underexplored opportunities for G-quadruplex (G4) DNA detection characterization. Here, we show a new switching mechanism that relies on recognition-driven disaggregation (on-signal) an ultrabright coumarin-quinazoline conjugate. synthesized probe selectively lights-up parallel G4 via disassembly its state, demonstrating outputs are easily integrable into label-free...
Mycobacterium tuberculosis ( Mtb ) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure antibiotics, resulting persistent infection. The global (TB) epidemic has been exacerbated emergence of mutant strains that are resistant frontline antibiotics. Thus, both phenotypic drug tolerance genetic resistance major obstacles successful TB therapy. Using a chemical approach...
G-quadruplex (G4) DNA structures are linked to key biological processes and human diseases. Small molecules that target specific G4 signal their presence would therefore be of great value as chemical research tools with potential further advance towards diagnostic therapeutic developments. However, the development these types compounds remain a challenge. In here, we have developed compound ability specifically certain c-MYC structure through fluorescence light-up mechanism. Despite...
G-quadruplex (G4) DNA structures are implicated in central biological processes and considered promising therapeutic targets because of their links to human diseases such as cancer. However, functional details how, when, why G4 form vivo largely missing leaving a knowledge gap that requires tailored chemical biology studies relevant live-cell model systems. Towards this end, we developed synthetic platform generate complementary probes centered around one the most effective selective...
G-Quadruplex (G4) DNA structures are important regulatory elements in central biological processes. Small molecules that selectively bind and stabilize G4 have therapeutic potential, there currently >1000 known ligands. Despite this, only two ligands ever made it to clinical trials. In this work, we synthesized several heterocyclic studied their interactions with G4s (e.g., from the c-MYC, c-KIT, BCL-2 promoters) using biochemical assays. We further effect of selected compounds on cell...
A reagent-free microwave-assisted decarboxylation procedure for carboxylic acid functionalized bicyclic 2-pyridones has been developed. This new method, based on microwave heating at 220 °C 600 seconds in N-methyl pyrrolidone (NMP), proved to be practical and very efficient, resulting decarboxylated near-quantitative yields. The products the intermediate form of methyl esters acids were screened their effect Aβ-peptide aggregation. Two out 21 described this study inhibited amyloid formation...
Pilicides prevent pili formation and thereby the development of bacterial biofilms in Escherichia coli. We have performed a comprehensive structure activity relationship (SAR) study dihydrothiazolo ring-fused 2-pyridone pilicide central fragment by varying all open positions. Orthogonal projections to latent structures discriminant analysis (OPLS-DA) was used distinguish active from inactive compounds which polarity proved be most important factor for discrimination. A quantitative SAR...
Pilicides and curlicides are compounds that block the formation of virulence factors pili curli, respectively. To facilitate studies interaction between these curli assembly systems, fluorescent pilicides have been synthesized. This was achieved by using a strategy based on structure-activity knowledge, in which key pilicide curlicide substituents ring-fused dihydrothiazolo 2-pyridone central fragment were replaced fluorophores. Several resulting had improved activities as measured pili-...
In order to understand in which biological processes the four-stranded G-quadruplex (G4) DNA structures play a role, it is important determine predicted regions can actually adopt G4 structure. Here, identify Schizosaccharomyces pombe that fold into structures, we first optimized quantitative PCR (qPCR) assay using stabilizer, PhenDC3. We call this method qPCR stop assay, and used screen for genomic DNA. The presence of stabilizers inhibited amplification 14/15 unexplored S. encompassed...
A self-assembled light-up rotor probe with outstanding sensitivity and selectivity for the <italic>c-MYC</italic> promoter G-quadruplex DNA is reported.
Molecular self-assembly is a powerful tool for the development of functional nanostructures with adaptive optical properties. However, in aqueous solution, hydrophobic effects monomeric units often afford supramolecular architectures typical side-by-side π-stacking arrangement compromised emissive Here, we report on role parallel DNA guanine quadruplexes (G4s) as disaggregating-capture systems capable coordinating zwitterionic fluorine-boron-based dye and promoting activation its...