A5018357131- Monoclonal and Polyclonal Antibodies Research
- Protein Structure and Dynamics
- Protein purification and stability
- RNA and protein synthesis mechanisms
- Alzheimer's disease research and treatments
- Enzyme Structure and Function
- Viral Infectious Diseases and Gene Expression in Insects
- Glycosylation and Glycoproteins Research
- vaccines and immunoinformatics approaches
- Computational Drug Discovery Methods
- Chemical Synthesis and Analysis
- RNA Research and Splicing
- RNA modifications and cancer
- Genetics, Aging, and Longevity in Model Organisms
- Transgenic Plants and Applications
- Click Chemistry and Applications
- Prion Diseases and Protein Misfolding
- Advanced Biosensing Techniques and Applications
- Heat shock proteins research
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Parkinson's Disease Mechanisms and Treatments
- Machine Learning in Bioinformatics
- Biosimilars and Bioanalytical Methods
- Enzyme Catalysis and Immobilization
- Microfluidic and Capillary Electrophoresis Applications
University of Cambridge
2016-2025
Abstract Protein aggregation is a complex process resulting in the formation of heterogeneous mixtures aggregate populations that are closely linked to neurodegenerative conditions, such as Alzheimer’s disease. Here, we find soluble aggregates formed at different stages amyloid beta (Aβ42) induce disruption lipid bilayers and an inflammatory response extents. Further, by using gradient ultracentrifugation assay, show smaller those most potent inducing membrane permeability effectively...
Intrinsically disordered proteins, defying the traditional protein structure-function paradigm, are a challenge to study experimentally. Because large part of our knowledge rests on computational predictions, it is crucial that their accuracy high. The Critical Assessment Intrinsic Disorder prediction (CAID) experiment was established as community-based blind test determine state art in intrinsically regions and subset residues involved binding. A total 43 methods were evaluated dataset 646...
Significance Parkinson’s disease is characterized by the presence in brain tissues of aberrant aggregates primarily formed protein α-synuclein. It has been difficult, however, to identify compounds capable preventing formation such deposits because complexity aggregation process By exploiting recently developed highly quantitative vitro assays, we a compound, squalamine, that blocks α-synuclein aggregation, and characterize its mode action. Our results show competing with for binding lipid...
The MobiDB (URL: mobidb.bio.unipd.it) database of protein disorder and mobility annotations has been significantly updated upgraded since its last major renewal in 2014. Several curated datasets for intrinsic folding upon binding have integrated from specialized databases. indirect evidence also expanded to better capture information available the PDB, such as high temperature residues X-ray structures overall conformational diversity. Novel nuclear magnetic resonance chemical shift data...
Abstract Monoclonal antibodies have emerged as key therapeutics. In particular, nanobodies, small, single-domain that are naturally expressed in camelids, rapidly gaining momentum following the approval of first nanobody drug 2019. Nonetheless, development these biologics therapeutics remains a challenge. Despite availability established vitro directed-evolution technologies relatively fast and cheap to deploy, gold standard for generating therapeutic discovery from animal immunization or...
Antibodies play essential roles in the immune system of vertebrates and are powerful tools research diagnostics. While hypervariable regions antibodies, which responsible for binding, can be readily identified from their amino acid sequence, it remains challenging to accurately pinpoint acids will contact with antigen (the paratope).In this work, we present a sequence-based probabilistic machine learning algorithm paratope prediction, named Parapred. Parapred uses deep-learning architecture...
Significance More than a decade ago, we put forward the “life on edge of solubility” hypothesis, according to which proteins are expressed in cellular environment at levels close their solubility limits. This observation was based analysis small number for and concentration information available time. To confirm this hypothesis have now taken advantage recent advances mass spectrometry that enabled proteome-wide protein concentrations both soluble insoluble forms. We been able show way vast...
Antibodies targeting Aβ42 are under intense scrutiny because of their therapeutic potential for Alzheimer's disease. To enable systematic searches, we present an "antibody scanning" strategy the generation a panel antibodies against Aβ42. Each antibody in is rationally designed to target specific linear epitope, with selected epitopes scanning sequence. By screening vitro identify microscopic steps aggregation process influenced by each antibody, two that specifically primary and secondary...
Significance Although antibodies can normally be obtained against a wide variety of antigens, there are still hard targets, including weakly immunogenic epitopes, which not readily amenable to existing production techniques. In addition, such techniques relatively time-consuming and costly, especially if the screening for specific epitope is required. this work we describe rational design method that enables one obtain targeting any within disordered protein or region. We show used target...
Antibodies represent essential tools in research and diagnostics are rapidly growing importance as therapeutics. Commonly used methods to obtain novel antibodies typically yield several candidates capable of engaging a given target. The development steps that follow, however, usually performed with only one or few since they can be resource demanding, thereby increasing the risk failure overall antibody discovery program. In particular, insufficient solubility, which may lead aggregation...
In Alzheimer's disease, aggregates of Aβ and tau in amyloid plaques neurofibrillary tangles spread progressively across brain tissues following a characteristic pattern, implying tissue-specific vulnerability to the disease. We report transcriptional analysis healthy brains identify an expression signature that predicts-at ages well before typical onset-the progression obtain this result by finding quantitative correlation between histopathological staging disease patterns proteins...
Despite major advances in antibody discovery technologies, the successful development of monoclonal antibodies (mAbs) into effective therapeutic and diagnostic agents can often be impeded by developability liabilities, such as poor expression, low solubility, high viscosity aggregation. Therefore, strategies to predict at early phases risk late-stage failure candidates are highly valuable. In this work, we employ silico solubility predictor CamSol design a library 17 variants humanized mAb...
Significance The accurate quantification of the amounts small oligomeric assemblies formed by amyloid β (Aβ) peptide represents a major challenge in Alzheimer’s field. There is therefore great interest development methods to specifically detect these oligomers distinguishing them from larger aggregates. availability will enable effective diagnostic and therapeutic interventions for this other diseases related protein misfolding aggregation. We describe here single-domain antibody able...
Abstract Intrinsic disorder (ID) in proteins is well-established structural biology, with increasing evidence for its involvement essential biological processes. As measuring dynamic ID behavior experimentally on a large scale remains difficult, scores of published predictors have tried to fill this gap. Unfortunately, their heterogeneity makes it difficult compare performance, confounding biologists wanting make an informed choice. To address issue, the Critical Assessment protein Disorder...
Solubility is a property of central importance for the use proteins in research molecular and cell biology applications biotechnology medicine. Since experimental methods measuring protein solubility are material intensive time consuming, computational have recently emerged to enable rapid inexpensive screening large libraries proteins, as it routinely required development pipelines. Here, we describe one such method include predictions effect pH on solubility. We illustrate resulting...
Antibody drugs should exhibit not only high-binding affinity for their target antigens but also favorable physicochemical drug-like properties. Such biophysical properties are essential the successful development of antibody drug products. The traditional approaches used in require significant experimentation to produce, optimize, and characterize many candidates. Therefore, it is attractive integrate new methods that can optimize process selecting antibodies with both desired target-binding...
Abstract Machine learning methods hold the promise to reduce costs and failure rates of conventional drug discovery pipelines. This issue is especially pressing for neurodegenerative diseases, where development disease-modifying drugs has been particularly challenging. To address this problem, we describe here a machine approach identify small molecule inhibitors α-synuclein aggregation, process implicated in Parkinson’s disease other synucleinopathies. Because proliferation aggregates takes...
Analysis methods based on simulations and optimization have been previously developed to estimate relative translation rates from next-generation sequencing data. Translation involves molecules chemical reactions, hence bioinformatics consistent with the laws of chemistry physics are more likely produce accurate results. Here, we derive simple equations kinetic principles measure translation-initiation rate, transcriptome-wide elongation individual codon ribosome profiling experiments. Our...