(Bio)synthesis and study of physico-chemical/biological properties of sinapoyl malate analogues: non-toxic and biobased anti-UV compounds for cosmetics industry – SINAPUV

This public-private project differs from current academic and industrial approaches in that it proposed to simultaneously study (1) a synthetic biology strategy for the engineering of microorganisms capable of producing chemical intermediates – coumaric (CA), ferulic (FA) and sinapic (SA) acids - from sugars, (2) the development of integrated fermentation and purification processes allowing the production of the acids, (3) the development of sustainable (chemo-)enzymatic pathways towards analogs of sinapoyl malate from the preceding acids (or their derivatives), (3) the study of their spectral/biological properties, (4) the determination of the toxicity of the most promising compounds, and (4) a life cycle assessment to identify the most economical and sustainable integrated process(es). To our knowledge, such a value chain from biomass to final active compound involving synthetic biology, microbiology, process engineering, green chemistry and the study of spectral/biological/toxicity properties remained unexplored. Bringing all these skills together within a single public-private consortium had great disruptive potential as it offered an integrated approach to accessing safer and more sustainable anti-UV compounds for the cosmetics industry.

New metabolic pathways allowing the biosynthesis of CA and FA have been optimized and inserted into microorganisms, the implementation of which in fermentation processes coupled with continuous extraction, has enabled the production of the acids with very promising titers. From these, and their corresponding aldehydes, the production of new families of anti-UV molecules (more than 150 compounds) via sustainable processes has been successfully achieved. Several candidates have been identified by Givaudan and are now undergoing the final tests before considering their commercialization. Other major players in cosmetics are currently testing several molecules, thus further expanding their marketing potential.

Five families of patents - covering microorganisms and metabolic pathways, as well as molecules and their synthesis process - have been filed. 28 scientific articles have been published and relate to all stages of the value chain developed within the framework of the project: synthetic biology, fermentation and coupling to an extraction process, sustainable syntheses, determination of the physico-chemical and biological properties of anti-UV molecules etc…

The multidisciplinary approach developed within the framework of SINAPUV (biomass -> synthons -> anti-UV molecules) has not only been validated through numerous patents and publications, but should also lead to the commercialization of several of the 150 analogues synthesized in the framework of the project. Another major advantage of the project lies in the fact that this approach can be adapted at will for any other molecule of interest and any other market. SINAPUV has thus demonstrated the relevance of an integrated multidisciplinary approach in the context of the biorefinery.

Five families of patents - covering microorganisms and metabolic pathways, as well as molecules and their synthesis process - have been filed. about thirty scientific articles have been published and relate to all the stages of the value chain developed within the framework of the project: synthetic biology, fermentation and coupling to an extraction process, sustainable syntheses, determination of physico-chemical properties and biological anti-UV molecules etc…

Anti-UV compounds represent a huge market in the cosmetics industry for their capacity to protect humans from sun damages. Unfortunately, current anti-UVs are being criticized for their toxicity towards the endocrine system of human, animals and fishes, and for their allergenicity; replacing them is thus a public health and environment preservation matter. Moreover, being fossil-based, these molecules are very difficult to degrade in the environment and their cost is extremely fluctuant. There is thus a high industrial/societal demand for cutting-edge technologies enabling the production of renewable and safer alternatives.

Nevertheless, to achieve this, one must overcome the following major hurdles: (1) availability of natural raw materials at low cost and large volumes, (2) highly selective and efficient (no/limited wastes, high yields and purity), sustainable, safe and cost-effective production process, (3) anti-UVs must exhibit complimentary biological activities as the marketing approval for compounds exhibiting only anti-UV activity is a complex, lengthy and costly procedure, (4) molecules must not exhibit any toxicity for the consumers, and be environmentally friendly, (5) molecules must (i) possess the required physico-chemical properties to be efficiently incorporated in the cosmetic formulation (e.g., hydrophilic-lipophilic balance (HLB)), and (ii) must be photostable for a period of time compatible with the destination of the cosmetic.

SINAPUV builds on the pioneer work of Chaire ABI and its partners from Purdue and Warwick universities that demonstrated that naturally occurring sinapoyl malate exhibits promising high anti-UV activity due to a very peculiar mechanism allowing the absorption of all wavelengths within the UV-B range. Unfortunately, sinapoyl malate extraction from plants is not feasible as it is present in very small quantities. SINAPUV is precisely designed to overcome not only this supply issue but also the hurdles described above by proposing a sustainable integrated approach that aims at producing biobased sinapoyl malate analogs directly from sugars and identifying the ones able to advantageously replace criticized commercial anti-UVs. To achieve this ambitious objective, the project relies on the simultaneous investigation of (1) a synthetic biology strategy for the engineering of microorganisms (bacteria and yeast) capable of producing two chemical intermediates - sinapic acid and sinapoyl malate - from carbohydrates, (2) the development of an integrated microbial production using the engineered strains and agro-industrial byproducts as fermentation medium, and purification processes allowing the production intensification of the intermediates, (3) the development of sustainable (chemo-)enzymatic pathways to sinapoyl malate analogs with tunable HLB from the previous intermediates, (3) the study of their spectral/biological properties both at the molecular and at the formulation level, (4) the determination of the toxicity of the most promising analogs, and (5) a life cycle assessment allowing the most durable analogs and integrated process(es) to be identified. Finally, the analogs exhibiting the highest anti-UV/biological activities and the lowest toxicity will be validated as proof of concept before their industrialization.

To rise to this challenge, academic actors and industrials have decided to build a private public partnership gathering all the scientific and industrial expertise required to fully address this multidisciplinary project. Internationally recognized French academic laboratories in synthetic biology (MICALIS), fermentation/downstream processing/green chemistry/LCA (Chaire ABI), and endocrine disruption (HSC) will work hand in hand with a start-up specialized in the construction of industry compliant genetically engineered micro-organisms (Abolis) and a world-leading company specialized in the production of biobased cosmetic ingredients (Givaudan Active Beauty).