Coupling enrichment methods with proteomics for understanding and treating disease

Abstract

Owing to recent advances in proteomics analytical methods and bioinformatics capabilities there is a growing trend toward using these capabilities for the development of drugs to treat human disease, including target and drug evaluation, understanding mechanisms of drug action, and biomarker discovery. Currently, the genetic sequences of many major organisms are available, which have helped greatly in characterizing proteomes in model animal systems and humans. Through proteomics, global profiles of different disease states can be characterized (e.g. changes in types and relative levels as well as changes in PTMs such as glycosylation or phosphorylation). Although intracellular proteomics can provide a broad overview of physiology of cells and tissues, it has been difficult to quantify the low abundance proteins which can be important for understanding the diseased states and treatment progression. For this reason, there is increasing interest in coupling comparative proteomics methods with subcellular fractionation and enrichment techniques for membranes, nucleus, phosphoproteome, glycoproteome as well as low abundance serum proteins. In this review, we will provide examples of where the utilization of different proteomics-coupled enrichment techniques has aided target and biomarker discovery, understanding the drug targeting mechanism, and mAb discovery. Taken together, these improvements will help to provide a better understanding of the pathophysiology of various diseases including cancer, autoimmunity, inflammation, cardiovascular disease, and neurological conditions, and in the design and development of better medicines for treating these afflictions.

Transcriptome profiling of NIH3T3 cell lines expressing opsin and the P23H opsin mutant identifies candidate drugs for the treatment of retinitis pigmentosa

“…In contrast to the profound transcriptome shift by T1, the lack of transcriptome alterations by treatment with compound 2 (T2) suggests that, in addition to transcriptome analysis, other systems biology techniques such as proteomics [68] are also needed for compound-target profiling. Recent work on a truncated mutant of CFTR (F508) clearly demonstrates that a global interactome remodeling occurs to CFTR interacting partners which are crucial for membrane localization [69].…”

Proteomic analysis of bronchoalveolar lavage fluid (BALF) from lung cancer patients using label-free mass spectrometry

“…This high dynamic range, spanning 10–12 orders of magnitude, is a result of abundant proteins, such as albumin, representing more than 99% of the total bulk mass of protein content [21]. Fractionation techniques, such as immunodepletion, can reduce this dynamic range, however biomarker discovery in blood remains a challenge [22], [23].…”

Urinary proteomics and metabolomics studies to monitor bladder health and urological diseases

“…So far the most attractive biofluids for biomarker discovery in bladder health and urological diseases are serum and urine [ 32 – 34 ]. Serum is a relatively accessible, stable and informative biofluid, making it ideal for early detection of systemic alteration in a wide range of diseases [ 35 , 36 ]. Monitoring of serum has several advantages mainly due to its stability and minimum dilution effect.…”