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SYNPEPTIDE Report Summary

Project ID: 613981
Funded under: FP7-KBBE
Country: Switzerland

Periodic Report Summary 2 - SYNPEPTIDE (Synthetic Biology for the production of functional peptides)

Project Context and Objectives:
Peptides are among the most versatile natural products that nature provides to cater for a broad set of biotechnological applications ranging from antibiotics to personal hygiene. Their diversity comes, among other origins, from a broad variety of posttranslational modifications (modifications to the peptide sequence that are only introduced once the amino acid backbone of the peptide has been fully assembled at the ribosome) that are used to provide additional functionality beyond to what is possible with the classic proteinogenic set of 20 amino acids. In Synpeptide, we want to recruit such additional functionality for rational molecular design purposes in order to facilitate the generation of synthetic peptides for application as pharmaceuticals.
We plan to generate large libraries of suitable peptides in order to identify peptides with novel activities, typically in the pharmaceutical domain (e.g, antimicrobial compounds). This has typically never been done with such rather complicated peptide structures.
In order to integrate posttranslational modifications into screening efforts, some rigorous standards have to be set and enforced so that design activities can proceed in an efficient way. Therefore, one of Synpeptide’s main tasks is to understand the molecular requirements of posttranslational modification – what are the molecular recognition events that allow the enzymes of posttranslational modifications to execute their functions, and what is important to enable several of such enzymes, recruited from systems that act on different types of peptides, to operate on the same peptide?
We also explore alternative options to increase peptide functionality, in particular the integration of non-canonical amino acids (i.e. enzymes that do not belong into the group of the 20 canonical amino acids which are encoded in the standard genetic code) into peptides. Such non-canonical amino acids can serve as entry points for subsequent (posttranslational) chemical modifications. Also here, it is extremely important to understand the molecular requirements for making these amino acids a part of the screening effort.
In order to be able to screen large numbers of different peptides for function, we need efficient screens to separate large numbers of inactive from small numbers of possibly active peptide molecules. This is the third major activity of Synpeptide, the setup of functional screens that allow miniaturizing and parallelizing the search for functional peptides. Systematic application of these assays is expected to help generating novel molecules for different applications.
Synpeptide also entertains activities from industrial partners, which benefit from the different activities of the consortium for the generation of novel pharmaceuticals and metabolic pathways.
Finally, the Synpeptide consortium would like to promote communication with stake holders in a broader sense in order to ensure a solid footing of the project in the heart of society.

Project Results:
Synpeptide has passed the 36 months mark and is entering the last year of its operation. Major results have been obtained in different work packages.
In work package 1, major advances towards understanding the molecular principles which guide the molecular recognition between the elements of the posttranslational machinery and the corresponding peptides have been made. By investigating archetypical representatives of two main classes of posttranslational machineries, it has become possible to delineate essential design considerations for integrating these machineries in screenings, and Synpeptide is on a good way to enable the combination of multiple such machineries in one cell, to operate on one peptide.
In work package 2, it has become clear that standard methods, allowing the precise insertion of non-canonical amino acids into peptides and proteins, maybe more difficult to implement in non-standard hosts than anticipated. Many such methods have been developed in E. coli, which is one of the hosts we are using to generate peptide libraries. However, a second host is Lactococcus lactis, a Gram-positive bacterium known for its production of the lantibiotic nisin (a posttranslationally modified peptide), and there application of standard methods such as stop codon suppression seems much more difficult. The reasons for that are not fully clear. However, alternative, less specific but still very effective methods can be brought to bear to this question.
Furthermore, if additional chemistry is to be performed on non-canonical amino acid carrying peptides, then rather elaborate adaptations have to be undertaken to screening assays. This is another main activity of WP2, and here we have shown proof of principle for all material steps.
Work in work packages 3 and 4 revolves around the implementation of large scale screening campaigns for peptides with novel functions. One such function is the generation of novel peptides with antimicrobial activities. Given the non-trivial mode of action of such peptides, designing robust assays for detection of function is challenging. We managed to implement such an assay for antimicrobials, characterized its performance parameters, adapted it to a variety of alternative experimental implementations, and, most importantly, applied it to a first major screening campaign. This campaign has indeed delivered a number of molecules with promising functions, and we are currently finishing characterization of these molecules while we plan the next campaigns.
Synpetide’s industrial partners work rather successfully and in-line with the original planning towards their respective goals.
Finally, Synpeptide is active in communicating its objectives and results to scientific and non-scientific communities. This includes activities such as high school information packages, filmed documentaries, and gamification.

Potential Impact:
The expected final results of Synpeptide are straightforward: Novel peptide antibiotics, novel pharmaceuticals, and a novel metabolic route to a high-value fine chemical. Of course, these results are highly ambitious and it is not clear if one or more of them can be reached in the allotted time.
If these goals can be reached, the socio-economic impact would be large. The increase of antimicrobial resistance, in particular in hospitals, in the face of a dearth of reserve antibiotics, is generally recognized as one of the major challenges for developed societies of the next 15 years. If this increase cannot be checked, major achievements of modern medicine will transit from blessings to life-threatening interventions.
Also, the aspired pharmaceutical would act with a rather novel principle of action, and, if successful, the ultimate arrival of such a compound on the market could be a major step towards the establishment of a compound class in the pharmaceutical sector –peptides - that is highly versatile and whose (known) shortcomings can – in our view – be overcome. Here, major revenues for the European pharmaceutical sector could become possible.
Finally, using biotechnology instead of chemistry on the way to high-value chemicals is a one possibility to increase the sustainability and profitability of chemical manufacturing processes. Though the case has to be made for each process again, the in general rather non-intensive production conditions using bacteria are considered a promising route. Implementing an example for a route which is generally considered to be very difficult would be an excellent step towards illustrating the major potential of biotechnology in fine chemical production.
As a second set of results, Synpeptide will contribute to the broadening of our understanding of the mechanisms of posttranslational modification of peptides. These peptides represent a very large group of natural compounds with a broad spectrum of activities, most importantly as antimicrobials. Even if Synpeptide will not directly deliver suitable molecules, the chance that in the future promising drug candidates will be isolated from this group is rather large. In fact, several such compounds are currently in clinical trials. This augurs well for novel molecules that will be identified in Synpeptide.
A third set of results will derive from Synpeptide’s outreach activities. Engaging laymen and stakeholders with activities such as high-school packages, gamification, exhibitions/movie festivals etc. represents a novel way of presenting science to the broader public. Our hope is that in this way the potential of these activities for the well-being of human society can be easily recognized and to some extent also demystified – in the sense that very practical objectives can be (potentially) reached by employing synthetic biology.
While these objectives remain in the future, Synpeptide has already had considerable impact, in particular in the scientific domain. As highlights, we should point out the activities of the Piel-lab, which already made valuable contributions to the understanding of the synthesis of a new and particularly promising peptide class and how it interacts with the posttranslational modification machinery.

List of Websites:


Sven Panke, (Professor of Bioprocess Engineering)
Tel.: +41 61 3873209
Fax: +41 61 3873994
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