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Cell-Like ‘Molecular Assembly Lines’ of Programmable Reaction Sequences as Game-Changers in Chemical Synthesis

Periodic Reporting for period 2 - CLASSY (Cell-Like ‘Molecular Assembly Lines’ of Programmable Reaction Sequences as Game-Changers in Chemical Synthesis)

Reporting period: 2020-11-01 to 2022-04-30

Inspired by the elegance with which living cells synthesize an enormous variety of complex products, CLASSY’s overarching objective is to create a microfluidic platform of microreactors, to emulate living cells in their capacity to self-regulate and catalyse programmable multistep synthetic processes. This microfluidic platform of microreactors will be able to synthesise complex molecules through programmable reaction sequences in molecular assembly lines. The main scientific challenges in creating cell-like molecular assembly lines include achieving an efficient compartmentalisation of the different steps for each reaction sequence and regulating such reaction sequences in a way that enables the same chemical reactor to produce a wide range of different molecules. Overcoming these challenges, however, will revolutionise chemical synthesis and provide a solution for close-to-zero waste streams and a sustainable ‘green chemical factory of the future’. Bringing together the expertise of leading scientists in systems chemistry, biocatalysis and microfluidics, the consortium has set three specific objectives that will be addressed over four years: (1) the development of a microfluidic platform for the immobilisation of multiple enzymes or peptide catalysts in microfluidic compartments, so to produce a versatile set of flow reactors that can catalyse a variety of single-step reactions; (2) the delivery of a new type of hybrid molecules capable to selectively control the catalysis of specific single-step reactions through programmable activation/deactivation of self-synthesising catalysts; (3) the study of microfluidic programming of cascade reactions by selective activation/deactivation of catalysts that operate sequentially.
During the second reporting period of the CLASSY project, significant results have been achieved. The main results that have been achieved include the following.
In relation to the first global objective of CLASSY, a second generation of microfluidic reactor has been developed, equipped with 16 individually addressable microreactors with a diameter of 5 mm each. In parallel, different strategies for enzyme immobilization within the microreactors have been developed, to enable single-step reactions with these compartmentalized catalysts. (Figure 1A). In a second line of work towards the second objective, we have combined various different, complementary strategies to achieve our goals. Key in all of them is to control the activity of peptides, NA sequences or NA-peptide hybrids, with the idea to modulate or switch them on/off depending on the conditions and requirements (Figure 1B). Finally, in order to address the possible selective activation/deactivation of catalysts in complex reaction sequences (Figure 1C), the important issue of controlling reactions by light in flow has given us the base to extend the above single-step reaction to enzymatic cascades. In a different approach, an organocatalyst is being combined with a biocatalyst.
Important steps towards the achievement of the CLASSY objectives are already underway. The results from the end of the second reporting period include having set up a second-generation (prototypical) microfluidic reactor to study compartmentalised catalysts. The new reactor design is more complex and was time-consuming, but provides much more flexibility in use, ensuring that the final outcome of the project will be of higher quality. The different strategies to control the activity of peptides, NA-peptide hybrids and enzymes have been successful for various reactions of interest, including the hydrolysis of the glycosidic bonds of simple sugars, length-controlled oligomerization reactions, Michael addition reactions, photodecarboxylations, hydrolase-catalyzed transformations, and alcohol oxidations, which will then be combined in cascade processes. The next steps are expected to lead to the generation of new scientific knowledge and technology to help achieving a high degree of programmability, selectivity, efficiency, sustainability and multi-functionality in cell-like systems that are able to perform catalysis. This will affect science and technology at two different levels. On one level, it will lead to improved understanding of the collective processes of living systems, which poses a formidable challenge that needs to be faced for a complete understanding of life. On a second level, applying this new understanding to the synthesis of functional systems and materials will revolutionize current approaches to chemical engineering, emphasizing energy balances, recycling of building blocks and multi-functionality. From an applied perspective, there is a growing industrial need to better understand and integrate complex physicochemical and biological phenomena relevant to the mastering of eco-efficient processes, which are currently subject to global threats, such as climate change and the crisis of raw material resources. The development of the new CLASSY technology is expected to trigger new business opportunities revolving around the commercialisation of catalytic technology and to create fertile ground future research endeavours. The advances that CLASSY will bring in the scientific and technological realm are expected to result in a key enabling technology for a cleaner and sustainable future, with the potential to bring long-term impacts on societal challenges, such as the development of less expensive drugs or the eradication of infectious diseases, by improving production methods and thus lowering costs.