A5004541105- Chemical Synthesis and Analysis
- Alzheimer's disease research and treatments
- Protein Structure and Dynamics
- Parkinson's Disease Mechanisms and Treatments
- Computational Drug Discovery Methods
- RNA and protein synthesis mechanisms
- Monoclonal and Polyclonal Antibodies Research
- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- Chromosomal and Genetic Variations
- Enzyme Structure and Function
- Receptor Mechanisms and Signaling
- Peptidase Inhibition and Analysis
- Genomics and Chromatin Dynamics
- Glycosylation and Glycoproteins Research
- Neuroscience and Neuropharmacology Research
- Cholinesterase and Neurodegenerative Diseases
- Protein Kinase Regulation and GTPase Signaling
- Cellular transport and secretion
- Viral Infectious Diseases and Gene Expression in Insects
- Biochemical and Structural Characterization
- RNA Interference and Gene Delivery
- Photosynthetic Processes and Mechanisms
- Mass Spectrometry Techniques and Applications
- Telomeres, Telomerase, and Senescence
University of Bath
2016-2025
The University of Queensland
2019-2025
Royal Brisbane and Women's Hospital
2023-2025
Emory University
2024
University of Zagreb
2024
University Medical Center Groningen
2024
University of Groningen
2024
Sheba Medical Center
2024
St George’s University Hospitals NHS Foundation Trust
2024
Barts Health NHS Trust
2024
The key pathogenic event in the onset of Alzheimer's disease (AD) is believed to be aggregation β-amyloid (Aβ) peptide into toxic oligomers. Molecules that interfere with this process may therefore act as therapeutic agents for treatment AD. N-Methylated peptides (meptides) are a general class inhibitors by binding one face aggregating but unable hydrogen bond on other face, because N-methyl group replacing backbone NH group. Here, we optimize structure meptide Aβ aggregation, starting KLVFF...
Activator protein-1 (AP-1) is a crucial transcription factor implicated in numerous cancers. For this reason, nine homologues of the AP-1 leucine zipper region have been characterized: Fos (c-Fos, FosB, Fra1, and Fra2), Jun (c-Jun, JunB, JunD), semirational library-designed winning peptides FosW JunW. The latter two were designed to specifically target c-Fos or c-Jun. They identified by using protein-fragment complementation assays combined with growth competition. This assay removes...
We have recovered terminal chromosome deletions of the X Drosophila [Df(1)RT; RT = receding tips] that break in various positions yellow gene (y) region and delete all distal DNA sequences. Terminal fragments are heterogeneous length. Molecular cloning sequencing revealed broken ends deleted chromosomes do not carry any telomeric sequences, yet chromatids fuse to one another. Moreover, we confirmed by sequence analysis 49 independently cloned from two lines collected at different times they...
Abstract The development of an intracellular peptide library screening platform is described to identify covalent transcription factor (TF) antagonists. Transcription Block Survival (TBS) assay and subsequent hit refinement previously produced potent but reversible antagonists the oncogenic TF cJun. TBS moves beyond a target binding readout ensure loss function by blocking TF‐DNA binding. Here, methodology significantly expanded highly selective inhibitors. A 131,072‐member probed containing...
Genetically encoded peptide library screening is a powerful strategy for discovering inhibitors of protein-protein and protein-DNA interactions. The Transcription Block Survival (TBS) assay enables the in vivo selection peptides that antagonise transcription factor (TF) binding by linking inhibition DNA-binding to E.coli survival. However, previous TBS implementations required laborious re-engineering mDHFR coding region each new target, limiting utility. Here, we present an enhanced...
A series of core mutations were introduced into beta-strand segments an immunoglobulin fold (the isolated first domain CD2, CD2.d1) to examine their influence on the rapidly formed intermediate state (I-state) which transiently accumulates in folding reaction [Parker, M. J., and Clarke, A. R. (1997) Biochemistry 36, 5786-5794]. The residue changes chemically conservative, each representing removal one or two methylene groups from aliphatic side chains. Predictably, destabilize folded with...
Protein-based therapeutics feature large interacting surfaces. Protein folding endows structural stability to localised surface epitopes, imparting high affinity and target specificity upon interactions with binding partners. However, short synthetic peptides sequences corresponding such protein epitopes are unstructured in water promiscuously bind proteins low specificity. Here we combine of proteins, cost rapid synthesis small molecules, towards meeting the significant challenge coiled...
Aggregation of α-synuclein (α-syn) into toxic fibrils is a pathogenic hallmark Parkinson disease (PD). Studies have focused largely on residues 71-82, yet most early-onset mutations are located between 46 and 53. A semirationally designed 209,952-member library based entirely this region was constructed, containing all wild-type changes associated with PD. Intracellular cell survival screening growth competition isolated 10-residue peptide antagonist that potently inhibits α-syn aggregation...
The energetic determinants that drive specific protein−protein interactions are not entirely understood. We describe simultaneous in vivo selection of and stable using homologous peptides which compete with protein libraries for an interaction a target molecule. Library members binding to their target, promoting cell growth, must outcompete competitor the (i.e., competition) evade competitors negative design). term this competitive design initiative (CANDI). combined CANDI protein-fragment...
The DNA binding activity of the transcriptional regulator activator protein-1 shows considerable promise as a target in cancer therapy. A number different strategies have been employed to inhibit function this protein with having demonstrated both vitro and vivo. Peptide-based therapeutics received renewed interest last few years, 37-amino acid peptides capable coiled coil dimerization domain Jun Fos derived. Here, we demonstrate how truncation semi-rational library design, followed by...
Abstract Tauopathies are characterised by the pathological accumulation of misfolded tau. The emerging view is that toxic tau species drive synaptic dysfunction and potentially propagation before measurable neurodegeneration evident, but underlying molecular events not well defined. Human non-mutated 0N4R (tau WT ) P301L mutant were expressed in mouse primary cortical neurons using adeno-associated viruses to monitor early changes function onset neuronal loss. In this model was...