Background

Bio-orthogonal reactions are essential tools used throughout basic research, in pharmaceutical (R&D and therapeutics) and biotechnology sectors, where they underpin key workflows for biomolecule tagging in live cells, target validation of small molecule drug leads through to the construction of antibody-drug-conjugates (ADCs) and peptide-oligonucleotide therapeutics (Figure 1).

Existing copper-free click chemistries are susceptible to side-reactions and their hydrophobicity can have an adverse impact on cell permeability. These reactions also produce product mixtures (different structural isomers), and typically require excess reagents which poses issues relating to the cost of manufacturing bioconjugates (e.g. ADCs).

In contrast, the classic copper-catalysed CuAAC ‘click reaction’ is fast, selective and regiospecific, producing a single 1,4-triazole product. One distinct limitation of CuAAC for life science applications is it typically requires micromolar [Cu] (20-500 M) to catalyze the reaction, which is typically toxic for many cell types. In addition, biomacromolecules contain numerous Cu-chelation sites, resulting in toxic residual Cu present in the final bioconjugate.

Therefore, access to efficient bio-orthogonal chemistries which produce a single product whilst minimizing or eliminating Cu toxicity would provide a new tagging bioconjugate platform technology for the life sciences.

Technology Overview

The University of Strathclyde has developed a unique variant of traditional CuAAC reaction, which exploits the unique reactivity of ynamines as an improved reagent for biomolecule tagging and bioconjugate synthesis. Recent results have identified ynamine click reagents which requires low levels - and in some cases no Cu(I) at all - of a Cu(I) catalyst, enabling selective formation of 1,4-triazole products. A patent application has been filed for the ynamine ligation platform which has the potential to circumvent Cu-toxicity and oxidative degradation associated with conventional CuAAC technology.

Our recent studies have shown that the bio-orthogonal reactivity of an ynamine click reaction is inherently tuneable according to its molecular environment (e.g., promoted by glutathione). This enables ynamine click reactions as a complementary reaction platform with other types of bio-orthogonal reactions. Furthermore, this opens up opportunities to use ynamine click chemistry as a platform to produce therapeutic bioconjugates with improved efficacy and safety profiles.

Stage of Development

The research team is currently expanding their suite of ynamine ‘click’ reagents and corresponding products which can:

(i) catalyse a chemical reaction (in this case, triazole formation); and

(ii) form a stable linker for the preparation of peptide-oligonucleotides, ADCs and other high-value bioconjugates

Benefits

Bio-orthogonal approach to functionalise biomolecules using biologically-relevant metal ions
Produce a single click product whilst minimising/eliminating bioconjugate oxidation and cellular toxicity associated with copper ions
Modular fluorogenic platform tuneable for the development of multi-colour imaging
Potential tool for real-time assessment of biomolecule production/tagging imaging and isolation

Opportunity

The first patent application to protect the technology was filed in July 2019. The team are now looking for Licensees and partners to develop the technology further and optimise various end-use applications.

A bio-orthogonal tagging platform for biomolecule labelling and bioconjugate synthesis

Patents

IP Status

Seeking