Receptor identification

Orphan ligand receptor deorphanization

Progress in the study of normal biological processes – or in understanding the mechanism of disease – has traditionally been hampered by the immense challenge in identifying the specific binding partners for a natural ligand or pathogen. Often these ‘orphan ligands’ bind to receptors or other types of proteins on the surface of human cells. Months or even years of research time can be lost using standard protein chips or proteomics/mass spec-based approaches to attempt to identify these interactions. Low success rates coupled with the potential for false positives can slow things even further.

Retrogenix cell microarrays are optimised for identifying physiologically-relevant cell surface interactions, vastly increasing the chances of finding a ligand’s receptor in just a matter of weeks. This is facilitating breakthroughs in medical research, including the recent identification of a key receptor involved in severe childhood malaria which was reported in the journal, Nature1.

Versatile across a range of ligands

Retrogenix identifies the cell surface receptors of a wide range of molecules ranging from purified proteins to more complex ligands such as whole cells. Retrogenix can uncover specific human receptors for:

  • natural soluble proteins and peptides
  • live viruses and virus-like particles (VLPs)
  • cell surface-derived ligands (i.e. those mediating cell:cell interactions)
  • whole cells expressing the ligand of interest
  • parasite-infected red blood cells
  • plasma samples from patients

Sensitive and specific

The highly-sensitive technology is capable of detecting micromolar affinity ligand-receptor interactions even in the absence of any amplification strategies. Our process includes a final confirmation screen which is undertaken to determine that the receptor ‘hit’ is reproducible and specific to the test ligand. Binding that is dependent on post-translational modifications to the target (such as glycosylation or folding) can also be detected – a real advantage over traditional protein microarrays.

Rapid determination of specific ligand-receptor interactions can be extremely cost-effective. An analysis by one of our pharmaceutical clients estimated that in-house methods required around 10x the investment of a Retrogenix screen to produce the same number of successful results. Achieving more meaningful results quicker can maintain a project’s momentum and can provide a competitive edge in being first to publish. It can also open up new opportunities for therapeutic development with obvious commercial benefits as well as advantages to patients.

To discuss a receptor identification project with a member of our science team please get in touch.

 

References:

Turner L et al. Severe malaria is associated with parasite binding to endothelial protein C receptor Nature 2013, 498:502. Click here to view the abstract and full text options.

Case study: Retrogenix identifies cell surface receptor associated with malaria – Nature paper

Collaborating with the University of Copenhagen, Retrogenix was able to successfully identify a key cell surface receptor associated with a severe form of childhood malaria. This opens up exciting new possibilities for drug and vaccine treatments for the disease, which is currently responsible for around half a million deaths in Africa every year.

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Case study: Retrogenix identifies interactions mediated by post-translational modifications

Research aimed at understanding the mechanism by which one form of malaria specifically attacks the placenta in pregnant women has resulted in the discovery of a potential new therapy that could be effective in a wide range of cancers. Key interactions meditated via distinct chondroitin sulphate (CS) chains were detected by Retrogenix in the study showing the real advantage over traditional protein arrays which lack the physiological processing that enables proteins to be properly folded, glycosylated and multimerised prior to screening.

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FAQ: “Which protein tags or labels are compatible with the Cell Microarray technology?”

As long as we can detect gain-of-binding to the cells in our microarrays we can screen any molecule. We have vast experience with anti-His, anti-Flag, anti-V5, anti-Fc, biotin-streptavidin, directly fluorescently tagged, and radiolabeled molecules.

We are also able to optimise the procedure for a new method should it be necessary to use a detection system that we have not encountered before. Please get in touch if you have a specific requirement.

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Pfizer
The University of Sheffield
Aveo Oncology - The Human Response
Theraclone Sciences
BioInvent
AstraZeneca
Bluebird Bio
The Center for Infectious Disease Research
Compugen Logo
The University of Copenhagen
Lund University
MedImmune
NIH - National Institutes of Health
The University of Pennsylvania
Scripps Florida - The Scripps Research Institute
Peptinnovate Ltd - Unlocking Nature's Potential
…working with you was exactly like working with an experienced and knowledgeable scientific collaborator. We had the same types of discussions and strategic planning sessions and I felt confident throughout that we were addressing the issues in the best way possible. It was fun and if I see the opportunity we would do this again.
Professor Mark Kahn, University of Pennsylvania