A5016529322- Hedgehog Signaling Pathway Studies
- Epigenetics and DNA Methylation
- Genomics and Chromatin Dynamics
- Peptidase Inhibition and Analysis
- RNA and protein synthesis mechanisms
- Structural and Chemical Analysis of Organic and Inorganic Compounds
- Synthesis and Reactivity of Sulfur-Containing Compounds
- DNA and Nucleic Acid Chemistry
- Bacterial Genetics and Biotechnology
- Viral Infections and Vectors
- Advanced biosensing and bioanalysis techniques
- Biochemical and Structural Characterization
- Synthesis and biological activity
- Ubiquitin and proteasome pathways
- Chemical Reaction Mechanisms
- ATP Synthase and ATPases Research
- Glycosylation and Glycoproteins Research
- Enzyme function and inhibition
- RNA Interference and Gene Delivery
- Research on Leishmaniasis Studies
- interferon and immune responses
- Synthesis of heterocyclic compounds
- Trypanosoma species research and implications
- Synthesis and Reactivity of Heterocycles
- Chemical Synthesis and Analysis
Imperial College London
2015-2024
Transnational Press London
2019
Bielefeld University
2011-2015
Humboldt-Universität zu Berlin
2007
Abstract Cancer gene therapy requires the design of non-viral vectors that carry genetic material and selectively deliver it with minimal toxicity. Non-viral based on cationic natural polymers can form electrostatic complexes negatively-charged polynucleotides such as microRNAs (miRNAs). Here we investigated physicochemical/biophysical properties chitosan–hsa-miRNA-145 (CS–miRNA) nanocomplexes biological responses MCF-7 breast cancer cells cultured in vitro . Self-assembled CS–miRNA were...
Abstract The promising drug target N -myristoyltransferase (NMT) catalyses an essential protein modification thought to occur exclusively at N-terminal glycines (Gly). Here, we present high-resolution human NMT1 structures co-crystallised with reactive cognate lipid and peptide substrates, revealing snapshots of the entire catalytic mechanism from initial final reaction states. Structural comparisons, together biochemical analysis, provide unforeseen details about how reaches a catalytically...
Several proteins, like transcription factors, bind to certain DNA sequences, thereby regulating biochemical pathways that determine the fate of corresponding cell. Due these key positions, it is indispensable analyze protein-DNA interactions and identify their mode action. Surface plasmon resonance a label-free method facilitates elucidation real-time kinetics biomolecular interactions. In this article, we focus on biosensor-based provide detailed guide how SPR can be utilized study binding...
The Sonic Hedgehog (Shh) signaling pathway plays a critical role during embryonic development and cancer progression. N-terminal palmitoylation of Shh by acyltransferase (Hhat) is essential for efficient signaling, raising interest in Hhat as novel drug target. A recently identified series dihydrothienopyridines has been proposed to function via this mode action; however, the lead compound (RUSKI-43) was subsequently shown possess cytotoxic activity unrelated canonical signaling. To identify...
Host interferon-induced transmembrane proteins (IFITMs) are broad-spectrum antiviral restriction factors. Of these, IFITM3 potently inhibits viruses that enter cells through acidic endosomes, many of which zoonotic and emerging with bats (order Chiroptera) as their natural hosts. We previously demonstrated microbat is antiviral. Here, we show bat IFITMs characterized by strong adaptive evolution identify a highly variable functionally important site—codon 70—within the conserved CD225 domain...
A highly accurate and versatile fluorescence polarisation assay for any enzyme adding or removing lipid posttranslational modifications, with the potential to accelerate drug discovery against these targets.
Abstract The mammalian membrane‐bound O ‐acyltransferase (MBOAT) superfamily is involved in biological processes including growth, development and appetite sensing. MBOATs are attractive drug targets cancer obesity; however, information on the binding site molecular mechanisms underlying small‐molecule inhibition elusive. This study reports rational of a photochemical probe to interrogate novel inhibitor human MBOAT Hedgehog acyltransferase (HHAT). Structure‐activity relationship...
2-Substituted N-acyl-piperidine is a widespread and important structural motif, found in approximately 500 currently available structures, present nearly 30 pharmaceutically active compounds. Restricted rotation of the acyl substituent such molecules can give rise to two distinct chemical environments. Here we demonstrate, using NMR studies density functional theory modeling lowest energy structures 5-acyl-6,7-dihydrothieno[3,2-c]pyridine derivatives, that amide E:Z equilibrium affected by...
-myristoylation is the covalent addition of a 14-carbon saturated fatty acid (myristate) to N-terminal glycine specific protein substrates by
Hedgehog signaling is involved in embryonic development and cancer growth. Functional activity of secreted proteins dependent on N-terminal palmitoylation, making the palmitoyl transferase acyltransferase (HHAT), a potential drug target series 4,5,6,7-tetrahydrothieno[3,2-c]pyridines have been identified as HHAT inhibitors. Based structural data, we designed synthesized 37 new analogues which profiled alongside 13 previously reported enzymatic cellular assays. Our results show that central...
Abstract The efrapeptin family of peptide antibiotics produced by the fungus Tolypocladium niveum , and neo‐efrapeptins from Geotrichum candidum are inhibitors F 1 ‐ATPase with promising antitumor, antimalaria, insecticidal activity. They rich in C α ‐dialkyl amino acids (Aib, Iva, Acc) contain one β‐alanine several pipecolic acid residues. C‐terminus bears an unusual heterocyclic cationic cap. efrapeptins C–G three analogues were synthesized using α‐azido carboxylic as masked derivatives....
The leishmaniases, caused by Leishmania species of protozoan parasites, are neglected tropical diseases with millions cases worldwide. Current therapeutic approaches limited toxicity, resistance, and cost. N-Myristoyltransferase (NMT), an enzyme ubiquitous essential in all eukaryotes, has been validated via genetic pharmacological methods as a promising anti-leishmanial target. Here we describe comprehensive structure–activity relationship (SAR) study thienopyrimidine series previously...
A combined approach based on isothermal titration calorimetry (ITC), fluorescence resonance energy transfer (FRET) experiments, circular dichroism spectroscopy (CD), atomic force microscopy (AFM) dynamic (DFS), and surface plasmon (SPR) was applied to elucidate the mechanism of protein-DNA complex formation impact protein dimerization DNA-binding domain PhoB (PhoB(DBD)). These insights can be translated related members family winged helix-turn-helix proteins. One central question assembly...
The Hedgehog pathway is a key developmental signaling but also implicated in many types of cancer. extracellular protein Sonic hedgehog (Shh) requires dual lipidation for functional signaling, whereby N-terminal palmitoylation performed by the enzyme acyltransferase (Hhat). Hhat an attractive target small-molecule inhibition to arrest and methods assaying activity are central understanding its function. However, all existing assays quantify peptides suffer limitations, such as safety...
The two-component regulatory system PhoR/PhoB induces the expression of several genes in response to phosphate starvation Escherichia coli. In order quantify these protein–DNA interactions and study time-resolved dynamics binding mechanism, specific recognition different oligonucleotide duplexes by DNA-binding domain PhoB (PhoBDBD) was analyzed using surface plasmon resonance. addition two point mutants PhoBDBDD196A PhoBDBDR219A were obtained DNA comparison wildtype PhoBDBD investigated....
Orthosteric inhibitors of the human heterodimeric DNA mismatch repair complex MutSbeta were identified by high-throughput screening. Following extensive hit confirmation to remove false positives, two series found give consistent activity free likely artefactual effects. Extensive profiling confirmed an ATP-competitive mode action, and X-ray crystallography showed occupying ATP-binding site MSH3.
Abstract The mammalian membrane-bound O -acyltransferase (MBOAT) superfamily is involved in biological processes including growth, development and appetite sensing. MBOATs are attractive drug targets cancer obesity; however, information on the binding site molecular mechanisms underlying small-molecule inhibition elusive. This study reports of a photochemical probe to interrogate human MBOAT Hedgehog acyltransferase (HHAT) based HHAT inhibitor RUSKI-201. Structure-activity relationship...
The mammalian membrane-bound