A publication in Nature Communications

Microfluidic production of synthetic cyclic peptides


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Thomas Toupy and Jean-Christophe Monbaliu (Center for Integrated Technology and Organic Synthesis - CiTOS, MolSys Research Unit) contributed to the development of an innovative method for the production of cyclic peptides within the frame of a collaboration with the Institut Pasteur in Lille. These cyclic peptides attract an increasingattention from the pharmaceutical industry for the development of new therapeutic agents. The results of this research have just been published in the journal Nature Communications(1).

C

yclic peptides are a class of chemical compounds with growing pharmaceutical prospects. The development of innovative preparation methods that can be transposed to the production scale is therefore a very significant and timely topic. "Cyclic peptides," explains Jean-Christophe Monbaliu, Director of the Center for Integrated Technology and Organic Synthesis - CiTOS laboratory (RU MolSys), "are particularly attractive for the development of new therapeutic agents because they are generally metabolically more stable and have a higher oral bioavailability than their linear counterparts." This very promising intrinsic potential nevertheless comes up against difficulties for their preparing in the lab, especially when the methods involve so-called "difficult" junctions. "There is a wide variety of methods for the production of cyclic peptides, but they are typically inefficient, slow and incompatible with production scale. In the current context of transitioning toward microfluidics and continuous flow technologies for the production of pharmaceutical compounds, and with our expertise in the field, we have started this very ambitious research program »

Thomas Toupy PhD student at CiTOS, and Jean-Christophe Monbaliu have contributed to the development of an innovative method for the production of these cyclic peptides within the framework of a long-term collaboration Dr. Oleg Melnyk, a peptide chemist and team leader at the Pasteur Institute of Lille. This method is based on a modification of the classical Native Chemical Ligation (NCL) method and its adaptation to microfluidic conditions. 

peptides cycliques

Microfluidic production of cyclic peptides

This study, whose results have just been published in the journal Nature Communications(1), proposes a new process that focuses on the application of microreactor technology and aims at the development of microfluidic strategies allowing the telescoping of multi-stage sequences based on NCL for the preparation of synthetic peptides. "This new process allows rapid and efficient cyclisation of peptides using a method derived from NCL under homogeneous microfluidic conditions.  With unprecedented cyclisation rates - less than 5 minutes - even for the most difficult junctions involving threonine, valine, isoleucine or proline, this technology opens the door to the rapid preparation of macrocyclic bioactive peptides, independently of the scale of production and guaranteeing a homogeneous purity profile", concludes Thomas Toupy.

This research research program has also triggered the inception of the µPEPS consortium at ULiège, associating Loic QUINTON (RU MolSys, FS), André MATAGNE (UR InBios, FS) and Tristan GILET (UR A&M, FSA) to the research efforts.

Scientific reference

(1) Ollivier N., Toupy T., Hartkoorn R., Desmet R., Monbaliu J.-C.M. & Melnyk O., Accelerated microfluidic native chemical ligation at difficult amino acids toward cyclic peptides, Nature Communications, volume 9, Article number: 2847 (2018)

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About Thomas TOUPY

Graduated with a Master in Chemical Sciences from ULiège (2017), Thomas is a doctoral student at CiTOS, where he develops synthetic methodologies for the construction of non-natural peptide architectures.

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About Jean-Christophe MONBALIU

Jean-Christophe (Ph.D. in Organic Chemistry, Université catholique de Louvain, 2008) joined the University of Liège in 2013 after several years of specialization for new processetechnologies applied to synthetic organic chemistry, among others at the Massachusetts Institute of Technology. He is currently Senior Lecturer within the RU Molsys (Faculty of Sciences). Hecreated the Center for Integrated Technology and Organic Synthesis (CiTOS) in 2013, where he is now working with his team to develop new methods in organic synthesis through the use of micro and mesofluidic reactors. Research programs at CiTOS revolve around the development of processes for the production of active pharmaceutical ingredients and the valorization of biosourced platform molecules.

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