Target ID - CDI Labs Applications

Empowering Drug Discovery and Development

Understand how a compound or molecule of interest interacts with human proteins at a proteome-wide scale.

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HuProt™ Microarray Can Identify the Biological Pathways and Mechanisms Underlying Human Disease

Target identification (ID) is a crucial step in the drug discovery and development process. It is aimed at identifying specific molecules or biological pathways that play a key role in a disease process and can be targeted by therapeutic interventions. HuProt™ is a powerful tool for target identification as it allows researchers to identify how a compound or molecule of interest interacts with human proteins at a proteome-wide scale, in a single experiment. HuProt can be used to asses protein binding to a wide variety of compounds or molecules including, proteins (protein-protein interactions), DNA, RNA, antibodies (antibody specificity studies), and many more.

Data from HuProt analysis (seromics or target identification data) can be integrated with data from other omics technologies, such as genomics, transcriptomics, and metabolomics, as part of systems biology approaches to studying complex biological systems. Integration of multi-omics data allows researchers to gain a compreensive understanding of disease mechanisms, identify novel drug targets, and develop personalized therapeutic strategies.

Protein-Protein Interactions

Protein-Protein Interactions

Featured Publication

Protein-protein interactions (PPIs) are essential for virtually all biological processes, governing cellular signaling, gene expression, metabolic pathways, and many other functions. These interactions occur when two or more proteins bind together to form complexes, enabling various cellular activities. Dysregulated PPIs are implicated in numerous diseases, including cancer, neurodegenerative disorders, infectious diseases, and autoimmune diseases. Understanding and targeting PPIs is a key strategy in today’s drug discovery process. By targeting specific interactions within PPI networks, researchers can identify novel drug targets and develop therapeutics that modulate disease-relevant pathways, ultimately leading to improved treatments and better patient care.

The featured publication demonstrates a conserved mechanism that TEAD1 trapping by mutant Lamin A/C at the nuclear membrane induces transcriptional dysregulation and structural maturation abnormality in cardiomyopathies, which can be treated through intervention in the Hippo signaling pathway. HuProt™ microarray screening identified a series of proteins more strongly bound to Q353R Lamin A/C than WT Lamin A/C. Among them, TEAD1 was shown to bind to Q353R Lamin A/C with an eightfold higher affinity than to WT Lamin A/C. This result was confirmed with Western blotting analysis.

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Protein-Nucleic Acid Interactions

Protein-nucleic acid interactions play a fundamental role in various biological processes, including gene expression, DNA replication, transcription, translation, and RNA processing. These interactions involve proteins binding to nucleic acids, such as DNA or RNA, to regulate their function and activity. Understanding protein-nucleic acid interactions and developing strategies to modulate these interactions hold great promise for advancing our understanding of gene regulation and for developing novel therapeutics for various diseases, including cancer, genetic disorders, and infectious diseases.

In the featured publication, HuProt™ microarray was used as part of a combined bioinformatics and protein microarray-based strategy to systematically characterize the human protein-DNA interactome. The paper identified 17,718 protein-DNA interactions (PDIs) between 460 DNA motifs predicted to regulate transcription and 4,191 human proteins of various functional classes. Many known PDIs for transcription factors (TFs) were recovered along with a large number of unanticipated PDIs for known TFs, as well as for previously uncharacterized TFs.

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Target Deconvolution / Target Discovery

target-discovery

Featured Publication

Target deconvolution is a process in drug discovery and development that involves identifying the specific molecular target(s) of a monoclonal or polyclonal antibody, bioactive compound or drug candidate. This process is crucial for understanding the mechanism of action of the compound, elucidating its effects on biological pathways, and assessing its potential therapeutic applications.

In disease research, it is not uncommon to identify antibodies without initially knowing their specific target. Monoclonal antibodies with unknown targets may have therapeutic potential for treating diseases or conditions for which the target antigen is unknown or poorly characterized. Further investigation and target identification efforts may reveal novel therapeutic opportunities based on the antibody's binding properties and biological effects.

HuProt™ microarray and VirScan™ PhIP-Seq were used in the featured publication which demonstrated high-affinity molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and the central nervous system protein glial cell adhesion molecule (GlialCAM) and provided structural and in vivo functional evidence for its relevance. The results provide a mechanistic link for the association between MS and EBV and could guide the development of new MS therapies.

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Antibody Specificity Validation

antibody-specification-validation

Featured Publication

Monoclonal antibody specificity validation is a crucial step in antibody development. Specificity testing validates that the antibody recognizes its intended target with high specificity while exhibiting minimal cross-reactivity with unrelated proteins or molecules.

In the featured publication, HuProt™ microarray was used as the primary validation tool to identify mAbs with high specificity for their cognate targets. A total of 122,662 antibodies were tested using 2 x 7 array format mini-chips, and subsequently 5,882 antibodies were tested on HuProt. The entire pipeline identified 1,406 highly validated immunoprecipitation- and/or immunoblotting-grade mouse monoclonal antibodies against 737 human transcription factors.

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Post-translational Modification Specificity Testing

Post-translational modifications (PTMs) are chemical modifications that occur on proteins after they have been synthesized. PTMs regulate protein activity, localization, and interactions by altering protein structure, stability, and interactions with other molecules. For example, phosphorylation can regulate enzyme activity, while ubiquitination targets proteins for degradation. As PTMs play crucial roles in protein function, targeting PTMs has emerged as a promising strategy in drug discovery. PTM specificity testing is crucial for validating binding to modified forms of proteins.

In the featured publication, multiplexed PTM reactions on HuProt™ microarrays were developed and applied to 102 TCGA ovarian tumor samples. Data integration and networks analysis led to the prediction that 19 tyrosine kinases were elevated and potentially responsible for the dysregulated pTyr signaling pathways in ovarian tumors. Elevated kinase activities of PTK2 and PTK2B were confirmed in several ovarian cancer cell lines.

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Chemically Induced Proximity (CIP)

Many disease treatments target a specific protein with the goal of blocking it, activating it, or destroying it (often called targeted degradation). The challenge with this methodology is that most protein targets don’t have sites that conventional medicines can efficiently bind to, resulting in an estimation that only 15% of human proteins are “druggable” with conventional medicines. Multispecific medicines overcome this challenge by using the principle of chemically induced proximity (CIP), in which they bring two things together, by using small molecules or chemical ligands. CIP is a powerful approach used in chemical biology and drug discovery to modulate protein function through the controlled assembly of protein complexes. CIP technologies, such as PROTACs (PROteolysis TArgeting Chimeras), LYTACs (LYsosome TArgeting Chimeras), and AUTOTACs (AUTOphagy- TArgeting Chimeras), leverage small molecules to induce the proximity of target proteins with specific cellular components, leading to their degradation or modification.

The featured publication outlines that the identification of protein substrates of ubiquitin E3 ligases in genetic/cellular experiments is challenging because of the complex milieu of the cell, the hundreds of E3 ligases present, and the potential for many indirect effects associated with loss- or gain-of-function of a particular enzyme. HuProt™ protein microarray technology was highlighted as offering an attractive alternative to standard cellular experiments because its application can rapidly and directly assess proteome wide enzyme-substrate relationships, even for low abundance proteins.

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