Controlling chemical reactivity with antibodies

How to repurpose IgG antibodies to boost different chemical reactions and create therapeutic molecules.

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Inside the small volume of a single cell a myriad of different species coexist. Despite this apparent confusion, these species react with each other in a very ordered and harmonic fashion, with chemical reactions happening in the right place and at the right time. One of the ways by which Nature achieves this high coordination is through proximity: the reactants are brought together into a confined space through highly evolved chemical recognition events and as a result their reaction is boosted.
The way Nature controls the chemical reactivity inside a cell is what any organic chemist could dream of: multiple reactions that can be specifically controlled in complex mixtures without any cross-reactivity. Inspired by this mechanism, we have demonstrated the possibility to use bivalent biomolecules (i.e. IgG antibodies) to induce proximity between reactants and thus control their chemical reactivity. 

To do this we took advantage of the versatility of synthetic DNA oligonucleotides and of the predictability of DNA-DNA interactions. More precisely, we employed two synthetic DNA oligonucleotides each of them modified at one end with a chemical reactive group. These two DNA strands were also modified at the other end with a recognition element (i.e. an antigen) for a specific IgG antibody. Under diluted conditions the two reactive groups cannot react with each other as their encounter is highly improbable. However, things change when the specific IgG antibody targeting the antigens at the ends of the DNA strands is present in solution. The IgG antibody in fact has two arms that allow for a very tight and specific binding to the antigen. This bivalent binding has the effect of bringing together in a very small volume the two reactive groups. As a result, the chemical reaction can occur and a product is obtained!

Because we can very easily change the antigens and the reactive groups on the DNA strands, we can make the system responsive to different antibodies and also trigger different reactions. Everything is triggered by the very specific recognition event between the antibody and the antigen so we can design parallel systems so that multiple reactions could be controlled in the same solution by different antibodies (Figure 1).

Figure 1. Orthogonal control of reactions mediated by different specific antibodies. Two systems with DNA templating pairs each labeled with a specific recognition element (DIG and DNP) were used in the same solution. One strand from each templating pair was also labeled with a different fluorophore to differentiate the products.

Finally, we explored the possibility to generate functional molecules such as therapeutic agents using these antibody-templated reactions. As a proof of principle we demonstrated the formation of an anticoagulant drug able to inhibit the activity of thrombin, a key enzyme of blood coagulation and an important target for the treatment of thrombosis. We demonstrated that a specific IgG antibody can trigger the formation of the anticoagulant agent, which was further proven to efficiently inhibit the activity of thrombin

In summary, we show that the function of IgG antibodies can be repurposed to control the reaction between two reactive groups in solution. IgG antibodies are remarkable biomarkers; they are the cues that provide us with indications about many diseases and how our immune system counter them. The potential ability of IgG antibodies to control chemical reactions would allow the formation of different molecules, ranging from imaging to therapeutic agents, only when a specific diagnostic IgG antibody is present in our body. We envision that this strategy might find applications in diagnostics and therapeutics.

Francesco Ricci

professor, University of Rome Tor Vergata

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