Application and Prospect of Proteomics in Pharmaceutical Research

1. Research on post-translational modification proteomics

Post-translational modifications of proteins are closely related to their functions. The known types of post-translational modifications of proteins in cells include phosphorylation of serine/threonine and tyrosine, acetylation of lysine, and ubiquitination. More than 400 types of post-translational modifications have been reported. Post-translational modification is one of the key links in the fine regulation of physiological activities of cells. For example, most of the activation of signaling pathways in organisms is related to phosphorylation modification, most of the protein degradation function is related to ubiquitination modification, and the regulation of functions in the nucleus is related to Modifications of histones are closely related. More and more studies have shown that the abnormal level of protein post-translational modification is closely related to the occurrence and development of certain diseases, such as the abnormal post-translational modification of Tau protein, mainly phosphorylation and glycosylation, is closely related to Alzheimer's disease.

Biological mass spectrometry is the core technology platform of proteomics research, and it plays an irreplaceable role in the identification of proteins, the discovery and verification of new modifications. When a post-translational modification occurs at an amino acid site of a protein, there is a mass shift at this site, which can be reflected in the primary and secondary spectra. For example, an acetylation modification on a lysine of a protein results in an increased mass shift of 42 Da at this lysine. Through the analysis of mass spectrometry data, the type of modification and the site of modification can be identified, so biological mass spectrometry technology can provide the most direct and reliable evidence for the discovery and verification of new protein modification types.

Histone modifications are involved in the regulation of many important cellular biological processes, such as activation or inhibition of gene transcription, DNA repair and other epigenetic phenomena, and are closely related to physiological phenomena such as tissue and organ development, cell development, differentiation and normal function. Studies have found that the abnormal regulation of histone modification is closely related to the occurrence and development of many diseases, including tumors, neurodegeneration, and autoimmunity. Due to the critical role that histone modifications play in many physiological and pathological processes; the study of histone modification biology has been a hotspot of biomedical research in the past 20 years.

Lysine crotonylation and tyrosine hydroxylation and proved that lysine crotonylation is closely related to gene activation and is closely related to the active genes of mouse spermatids in the late meiosis, suggesting that this modification may be related to Novel epigenetic regulators closely related to sperm development.

Among many types of lysine modifications, lysine methylation is crucial for the regulation of cellular chromatin function, and methylation-modifying enzymes are also important drug targets. However, due to technical limitations, the enrichment and systematic identification of non-histone lysine monomethylation substrates is a current research difficulty, which greatly limits the research on the biological function of lysine methylation modification.

Second, the application of proteomics in the field of drug research

In recent years, with the rapid development of proteomics technology, this technology has also been applied to the field of drug research. In particular, it has played a great advantage in the research of drug target protein confirmation, drug action mechanism, and search for diseased genes; in the process of drug treatment, proteomics can also be used to evaluate drug efficacy, which significantly improves drug discovery. s efficiency.

Currently, there are two main strategies for drug development: target-based drug discovery and phenotypic-based drug discovery. The difference between the two is: drug discovery based on phenotypic changes is to explore the physiological and biochemical manifestations caused by the active compound and the target protein that causes the manifestations under the premise of known phenotypic changes and efficacy; Under the premise that the biological function of the target protein is known, the compound library is screened for lead compounds that can interact with the target protein and change its biological activity.

The purpose of these two strategies is to discover active compounds and their target proteins, and on this basis, carry out structural modification and optimization of active compounds, and conduct related preclinical studies on structure-activity relationship, pharmacology, and toxicology. In both drug research strategies, proteomics plays an irreplaceable role. At present, proteomics can identify 8,000 to 10,000 proteins in a single cell clone within one day of mass spectrometry acquisition. Therefore, proteomics technology has the advantages of high efficiency and high accuracy in target identification. By comparing the differences in the expression level of the whole protein between the "drug" group and the control group, and carrying out bioinformatics analysis on these differential proteins, the effect of the "drug" on the physiological function of cells can be found, which will help to deepen the understanding of the Knowledge of the uses and mechanisms of "drugs".

At the same time, in terms of finding drug targets, proteomics can effectively enrich the proteins that interact with drugs through competitive experiments, and identify the target proteins through mass spectrometry analysis, which is currently unachievable by traditional biological methods. Proteomics can not only identify drug targets, but also further explore the impact of drug-target interactions on protein-protein interactions.

3. Outlook

Biomedical research has experienced the development of disciplines from physiology in the early 20th century to molecular biology in the mid-20th century to systems biology in the early 21st century. These three research fields have their own characteristics and limitations.

Physiology mainly focuses on the study of the function and metabolism of organs and tissues but lacks the identification and differentiation of intracellular components; molecular biology mainly focuses on the identification and functional research of biological components, but the disadvantage is the difference between the different molecules studied. However, systems biology mainly focuses on the integrated analysis of multidisciplinary research fields but is limited by the quality and reliability of the data. Therefore, the exchanges of the three disciplines can promote and complement each other to a large extent, and effectively accelerate the research of life sciences, which is also the development direction of life sciences in the future.

In addition to genomes and proteomes, other omics studies are also being conducted in the field of life sciences, including transcriptomics, metabolomics, etc., collectively referred to as panomics. The increasing availability of experimental data in life sciences and the rapid development of computer technology all herald the arrival of the era of big data in life sciences. Life science research in the era of big data not only shows a rapid growth of orders of magnitude in experimental data, but also the complexity of the data increases dramatically. The huge bioinformatics platform also provides ultra-high speed and efficiency for the sorting and analysis of big data. .

Proteomics research in the era of big data can not only absorb and imitate the research methods of other omics, but also integrate and analyze with other big data, so as to mine potentially more meaningful information, so this is proteomics. At the same time, if proteomics cannot be further improved and reasonably integrated with other big data, it will easily be submerged in the ocean of big data, so the era of big data is also a big challenge for proteomics.

For proteomics services, proteomic services include molecular weight determination, MSn, LC-MS, high resolution MS, Maldi-TOF intact protein analysis, protein identification by proteolytic digest, nano LC-MS/MS and database search, protein quantification via label free, TMT and ITRAQ based protein quantification, standard and long column capillary chromatography, and more.

With the advent of the era of precision medicine, proteomics will become one of the most effective methods for finding molecular markers of disease and drug targets, allowing people to break through the shackles of past research and develop new, more precise and more complete From the perspective of understanding the occurrence and development of diseases, accurately find the causes of diseases and therapeutic targets, and finally achieve the purpose of personalized and precise diagnosis and treatment. In the clinical diagnosis and treatment of major human diseases such as cancer, Alzheimer's disease, diabetes, etc., proteomics technology has very broad application prospects, and can also provide early diagnosis, drug target discovery, treatment and prognosis of related diseases. important foundation.

However, there is still a long way to go for proteomics to be applied to clinical therapeutic research on a large scale. The information of the proteome can only exert its advantages when it penetrates into specific biological problems. In order to fully understand the function and role of proteins in the human body, it is necessary to fully understand the isoforms and modified functions of proteins in the human body. The function can also be achieved through protein complexes and protein interaction networks, so the high-throughput and efficient study of protein complexes and protein interaction networks in the human body is a higher stage of proteomics. Therefore, in a sense, the research of proteomics is "endless".

AxisPharm is a San Diego based bioanalytical LC/MS/MS service provider with more than 25 years of experience in the field. Our bioanalytical chemistry department specializes in developing and validating robust bioanalytical methods for PK/TK sample analysis of small molecules, proteins, peptides, and metabolites using LCMS/MS (HPLC, UPLC, on-line SPE), HPLC/UV, and HPLC/FL. We have experience analyzing API and metabolites in various biological matrices and can provide bioanalytical support throughout all the stages of drug development.

References:
https://axispharm.com/proteomics-services-protein-identification-quantification-and-ptm-analysis/

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This release was published on openPR.