A Novel Class of Precision Biologics

The SelekTx Drug Discovery Platform utilises carefully designed selection strategies to identify highly-selective Selektide binding proteins from our large, diverse libraries against the disease target using natively expressed receptors in disease associated cells. Targeting the endogenously expressed receptor in cancer, immune and metabolic cell lines is a key feature of the platform. 

Native presentation of the receptor ensures that the target GPCR is optimally presented to library binders in its functional conformation in its native environment during the selection rounds, providing the maximum opportunity to identify Selektides that not only bind the receptor but that functionally modulate the receptor through correct structural recognition. 

These strategies are powered by combinations of disease cells in concert with recombinantly overexpressed target receptors in human cell lines with panels of non-expressing cells & CRISPR knockout cell lines created at SelekTx, specific to each discovery campaign. 

Combining cancerous, inflammatory and metabolically relevant disease cells enables us to effectively remove cross-reactive binders during selection and identify the most selective drug candidates to address the limitations of drugs with off target side effects. 

Utilising endogenous expression of GPCR targets on disease associated cells drives selection of highly specific, selective Selektides for optimal therapeutic discovery.

The SelekTx Drug Discovery Platform utilises carefully designed selection strategies to identify highly-selective Selektide binding proteins from our large, diverse libraries against the disease target using natively expressed receptors in disease associated cells. Targeting the endogenously expressed receptor in cancer, immune and metabolic cell lines is a key feature of EndoSelekt. 

This ensures that the target GPCR is optimally presented to library binders in its correct conformation in its native environment during the selection rounds, providing the maximum opportunity to identify Selektides that not only bind the receptor but that functionally modulate the receptor through correct structural recognition. 

These strategies are powered by combinations of recombinantly overexpressed target receptors in human cell lines with panels of non-expressing cells & CRISPR knockout cell lines created at SelekTx, specific to each discovery campaign. 

Combining these engineered cell lines with native receptor expressing, cancer, inflammatory and metabolically relevant disease cells enables us to effectively remove cross-reactive binders during selection and identify the most selective drug candidates to address the limitations of drugs with off target side effects. 

Proprietary computational analysis of selection outputs and AI-guided structure targeting prediction and candidate ranking algorithms.

We have built a modular pipeline with R and Python coding scripts underpinning comparative data analysis between selections on different cell lines helping to identify stringent selectivity cut off values to ensure potential cross-reactive sequence populations are not considered. 

This pipeline provides additional freedom to integrate the fast-evolving structural modelling AI-driven tools such as AlphaFold and RosettaFold. This is then leveraged to derive tailored results and visualizations focused on extracellular domain (ECD) by targeting knowledge-driven outputs with AI modules/nodes to filter, select and rank the hit affinity peptides. 

With IntelliSelekt we enhance the outputs from AI-driven modelling by developing visualization scripts using Matplotlib and PyMOL tools, providing detailed insights into protein-ligand interactions.

Functional assay matrix to define mechanistic attributes 

identifying agonist, antagonist and inverse agonist potential with kinetic profiling.

Is a multimodal assay matrix designed to identify and rank key behavioural attributes of Selektides produced by EndoSelekt and IntelliSelekt. 

Agonist, antagonist or inverse agonist activity at the target receptor is measured using a comprehensive suite of in vitro and cellular assays including:

1.   High speed DNA synthesis, protein expression purification 

2.   Flow cytometry & membrane protein array selectivity screening 

3.   Reporter gene luciferase activation assays

4.   cAMP and Glucose accumulation assays 

5.   Calcium influx assays

6.   Transcription factor phosphorylation assays 

7.   Cell motility phenotyping and cellular imaging 

The lead candidate Selektides having the desired functional properties from this matrix are then finally further assessed using cryo-electron microscopy structural analysis to determine the specific structural relationship between the Selektide and receptor target. 

Resolving the structural relationship between Selektide and receptor is a key feature of FunctionSelekt to lead to IND enabling status.

The flexibility of the Selektide platform provides the opportunity to develop Selektide monomers, bispecifics,  multimers, Fc fusion and conjugated peptide formats. 

The flexibility of the scaffold supports a series of unique drug formats for targeted therapy approaches.

1.   Monomeric Selektide scaffolds – 10 kDa monomeric proteins with a single constrained peptide loop for target binding with optional modifications including PK extension and cargo delivery functions. 

2.   Bispecific Selektide scaffolds – 10 kDa monomeric proteins with two binding domains for simultaneous binding to distinct target epitopes. 

3.   Dimeric and multimeric constructs of Selektide scaffolds for multi-target engagement and immune recruitment. 

4.   Fc fusion constructs of Selektide binders for long circulating half-life and effector functions. 

5.   Chemical synthesis of individual constrained peptides with suitable potency characteristics independent of scaffold presentation. 

This format-flexible approach enables the productivity of the EndoSelekt-IntelliSelekt-FunctionSelekt pipeline.