Integral membrane proteins
Integral membrane proteins, such as G protein-coupled receptors (GPCRs) and Ion channels perform numerous biological functions. However, ligand discovery for membrane proteins is highly challenging, because a natural cellular environment is often necessary to maintain protein structure and function.
Our DEL – Integral Membrane Protein service takes advantage of our unique homogeneous assay with read out based on DNA ligation, PCR and DNA sequencing. The biotinylated target protein formulated in nanodiscs or detergent is mixed with DEL and biotin binding protein (BBP) conjugated to DNA. DEL members binding to the target are identified by ligating the DNA associated to the target (via the biotin BBP interaction) and the DNA associated to the DEL member. The ligated DNA is amplified by PCR and its identity is determined by DNA sequencing.
Service in brief
- 1. You provide the purified biotinylated target protein formulated in nanodiscs or detergent (micrograms)
- 2. We conduct the screening, perform the analysis and provide a report, including hit list with chemical structure information
Timelines
Screening: 4 weeks
Keys
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Screen requires small quantities of purified biotinylated membrane protein formulated in nanodiscs or detergent (micrograms) -
Screen is conducted with many conditions in parallel
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Screen is conducted in a homogeneous assay to avoid matrix binders and target denaturation
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Identifies hits and hit families
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Instant structure-activity relationship (SAR)
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Instant MOA of hits by screening in the presence of a known ligand or resynthesized hit
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High success rate (>75%)
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Low false positive rates (100% match between DNA code and compound)
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Applicable across disease areas and target classes
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Straightforward and transparent data analysis
Business Model
- Simple fee-based plan with no reach-through and royalty payments
- Hit exclusivity
- The compensation plan comprises a total of 2 payments
- Screening Fee – scales with screening slots
- Chemical Series Nomination Fee
- The project flow is rapid and straightforward:
- Client provides the target protein (100 micrograms)
- Vipergen performs one or two rounds of screening, each under varying conditions and with different libraries.
- After each screening round, Vipergen delivers a hit list and report, including metrics from screens and chemical structure information
- Hits are reserved for client for 1 year
- Client may resynthesize and test hits in relevant assays and use data for 1 year
- Client may nominate Chemical Series for 1 year
- Vipergen assigns its rights to Nominated Chemical Series and these become exclusive for client
DELs
Vipergen’s high fidelity DELs are synthesized using robust chemistry and with a purification steps after each chemical transformation, thus providing 100% correspondence between code and compound (no truncates).
Key drivers for library design
- Chemical diversity
- Physicochemical properties
- Fidelity
- Hit resynthesis (off DNA)
| Parameter | Lib046 | Lib056 | Lib081 |
|---|---|---|---|
| Size (million of compounds) | 445 | 522 | 381 |
| Chemistries |
|
|
|
| Compounds w 1 cyclic, tertiary amide | 49% | 47% | 52% |
| Compounds w 2 cyclic, tertiary amides | – | 42% | 33% |
| Total number of building blocks (#) | 1507 | 1327 | 1138 |
| Designer building blocks (#) | 979 | 755 | 617 |
| Scaffolds (#) | 368 | 343 | 295 |
| Toxicophores (%) | 1.1 | 0.4 | 1.1 |
| Molecular weight (avg) | 612 | 529 | 525 |
| cLogP (avg) | 2.8 | 0.75 | 0.9 |
| HBA (avg) | 8.7 | 6.3 | 6.2 |
| HBD (avg) | 2.8 | 2.8 | 2.9 |
| Rotatable bonds (avg) | 10.7 | 8.8 | 8.9 |
| TPSA (avg) | 153 | 139 | 137 |
| Fsp3 (avg) | 0.5 | 0.6 | 0.6 |
Target classes
- Kinases
- Oxidoreductase Proteases
- Hydrolases
- Isomerases
- Transferases
- Lyases
- Phosphatases
- Transcription factors
- Synthases
- E3 biquitin ligases
- Deubiquitinases (DUBs)
- Helicases
- Polymerases
- Nucleotide exchange factors
- Decarboxylases
- Ligases
- Integral membrane proteins
- G protein-coupled receptors (GPCRs)
- Ion channels
- Single-pass membrane proteins
- Nuclear receptors
- Cytosolic receptors
- Extracellular receptors
- Transcription factors
- E3 ligases
- Deubiquitinases (DUBs)
- Antibodies
- Cytokines
- Interleukins
- Growth factors
- Carrier proteins
- Adaptor proteins
- Oncoproteins
- Histone binders
- Methyl transferases
- Acetyltransferase
- Demethylases
- Deacetylases
- Viral proteins (enzymes and coat proteins)
- Bacterial proteins (enzymes and receptors)
- Fungal proteins (enzymes and receptors)