Recent Developments in Proteomics Research
The term proteomics – used to describe the large-scale characterization of proteins – was coined in the 1990’s by Mark Wilkins, who was a PhD student at the time. Since then, the field has gained momentum and can now be subdivided into various areas of study – from protein expression profiling and proteome mining to structural and functional proteomics and protein interactions. A cell’s proteome reflects the immediate environment in which it is studied, and various proteomics techniques can be exploited to identify the “set” of proteins within a cell, in turn helping to create an intricate map of the cell, to determine the exact location of individual proteins.
Here, we take a closer look at some recent developments in the world of proteomics research.
Novel Approach Yields Potential Drug Candidate for Bladder Cancer
An international collaboration of scientists has developed a new approach to molecular drug design, allowing for the production of a promising bladder cancer drug. The team applied the "intrinsically disordered proteins" (IDP) concept to their work. Intrinsically disordered proteins make up > 50% of the human proteome – their ability to adapt and change shape allows them to bind different surfaces, and in some cases such as this, result in a gain of function. This concept could explain why drugs based on a “lock and key” approach have limited clinical success. When tested in clinical trials, the novel drug induced rapid shedding of cancer cells and resulted in a significant reduction in tumor size.
“This research is … extremely exciting as the clinical trials show great impact in reducing tumor size in people with this form of bladder cancer without any side effects,” said Ken H Mok, associate professor in Trinity's School of Biochemistry and Immunology and the Trinity Biomedical Sciences Institute. "From a scientific perspective – and with a nod to the great potential for other therapeutic discoveries – it is also extremely exciting to have contributed to an entirely new approach to molecular drug design.”
Reference: Brisuda A, Ho JCS, Kandiyal PS, et al. Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex. Nat Commun. 2021;12(1):3427. doi: 10.1038/s41467-021-23748-y
A Blood Test for the Early Detection of Alzheimer's DiseaseIn order to diagnose Alzheimer’s disease (AD), clinicians currently rely on a combination of techniques including cognitive tests, brain imaging and lumbar puncture. These methods are expensive, invasive and frequently unavailable in many countries. To help to address the shortfalls associated with these methods, researchers have designed a high-performance, blood-based test for AD. The test relies on a biomarker panel and a system that distinguishes between patients with early, intermediate and late stages of AD. This test can therefore be used for diagnosis and disease progression monitoring.
"With the advancement of ultrasensitive blood-based protein detection technology, we have developed a simple, non-invasive, and accurate diagnostic solution for AD, which will greatly facilitate population-scale screening and staging of the disease," said Prof. Nancy Ip, Morningside professor of life science and the director of the State Key Laboratory of Molecular Neuroscience at HKUST.
Reference: Jiang Y, Zhou X, Ip FC, et al. Large-scale plasma proteomic profiling identifies a high-performance biomarker panel for Alzheimer’s disease screening and staging. Alzheimers Dement. 2021. doi: 10.1002/alz.12369
Could Cone Snail Venom Be Used To Treat Severe Malaria
Severe forms of malaria can be deadly even after treatment with currently available parasite-killing drugs. This is due to persistent cyto-adhesion of infected erythrocytes despite the parasites, that reside within the host cells, being dead. Anti-adhesion drugs may therefore hold the key to significantly improving survival rates. New research into the venom produced by Conus nux, a species of sea snail, has revealed its’ ability to disrupt specific interactions (protein–polysaccharide and protein–protein) that contribute to the pathology of malaria. These conotoxins may therefore be utilized in the development of novel and cost-effective anti-adhesion drugs or blockade-therapy designed treat severe malaria.
"Among the more than 850 species of cone snails there are hundreds of thousands of diverse venom exopeptides that have been selected throughout several million years of evolution to capture their prey and deter predators," said Frank Marí, PhD, corresponding author and senior advisor for biochemical sciences at the National Institute of Standards and Technology. "They do so by targeting several surface proteins present in target excitable cells. This immense biomolecular library of conopeptides can be explored for potential use as therapeutic leads against persistent and emerging diseases affecting non-excitable systems."
Reference: Padilla A, Dovell S, Chesnokov O, Hoggard M, Oleinikov AV, Marí F. Conus venom fractions inhibit the adhesion of Plasmodium falciparum erythrocyte membrane protein 1 domains to the host vascular receptors. J. Proteom. 2021;234:104083. doi: 10.1016/j.jprot.2020.104083
A research team from the Skoltech Institute of Science and Technology has developed a mass spectrometry-based diagnostic approach to detect the vertical transmission of SARS-CoV-2 from mother to fetus. The study, published in Viruses, assessed the case of a healthy 27-year-old woman that became "moderately sick" with COVID-19 at her 21st week of gestation. The child was delivered prematurely (26th week of gestation) and died shortly after. The study’s senior author, Evgeny Nikolaev, explained that the proteomics-based method was the most reliable method to use to determine vertical transmission, as it can identify viral proteins with 100% confidence – something that cannot be achieved using other methods, such as PCR.
"We cut the N and S proteins isolated from the virus using a particular enzyme (trypsin) and detect them on a mass spectrometer. We use a standard ionization method – electrospray. Then, we search for the specific sequence of amino acids in mass-spectrometry data, using standard proteomic techniques," said Evgeny Nikolaev, professor at the Center for Computational and Data-Intensive Science and Engineering, Skoltech Institute of Science and Technology.
Reference: Sukhikh G, Petrova U, Prikhodko A, et al. Vertical transmission of SARS-CoV-2 in second trimester associated with severe neonatal pathology. Viruses. 2021;13(3):447. doi: 10.3390/v13030447
Probing the Proteomic Landscape of Cancer To Discover Drug Targets
Scientists from Baylor College of Medicine have demonstrated that by analyzing protein data from aggressive human cancers it is possible to uncover key drivers of disease that could be exploited as therapeutic targets. The team investigated seven specific cancer types (breast, colon, renal, lung, ovarian, uterine and glioma) and looked to determine "proteomic signatures" associated with clinical measures of aggressive disease. Some signatures were shared between cancer types and included cellular pathways of altered metabolism.
"Our experiments provided proof-of-concept that proteomics analysis is a useful strategy not only to better understand what drives cancer, but to identify new ways to control it or eliminate it," said Diana Monsivais, assistant professor of pathology and immunology, Baylor College of Medicine.
Reference: Monsivais D, Vasquez YM, Chen F, et al. Mass-spectrometry-based proteomic correlates of grade and stage reveal pathways and kinases associated with aggressive human cancers. Oncogene. 2021;40(11):2081-2095. doi: 10.1038/s41388-021-01681-0