Polyphenol-Bearing Probes for Unveiling Polyphenol-Proteins Interactions – Towards Polyphenol-Based Therapeutics? – POLYPHENOLPROT

Polyphenols that are present in dietary plants are claimed to express human health-protecting effects because of their abilities to ameliorate age-related conditions leading to cardiovascular diseases, cancer, neurological and metabolic disorders, as well as skin and bone deteriorations. This is notably one of the main reasons why it is nowadays highly recommended by the World Health Organization to eat five servings of fruits and vegetables per day, a health message that is regularly relayed by the Ministry of Health in the public media. Paradoxically, the potential clinical use of these natural products as pharmaceutical drugs is still far from being exploited, mainly because of concerns regarding their lack of selectivity, possible toxicity and poor bioavailability that merely relegate polyphenols as interesting natural antioxidants for food supplementation, parapharmaceutical uses or cosmetic applications. Nevertheless, there is today compelling evidence that the mechanisms by which polyphenols express their protective (and possibly curative) actions against several pathologies are not simply due to their antioxidant properties, but also to their aptitude to bind to target proteins. However, the nature of the proteins involved and the mechanisms by which these molecular interactions translate into positive biological responses remain obscure, and the archetypal multi-target nature of polyphenols is rarely taken into consideration in investigations aimed at evaluating their activities. This situation constitutes a serious drawback toward the full understanding of the true biological effects of dietary polyphenols, and therefore toward any development of polyphenol-based or -inspired agents as viable therapeutics capable of expressing systemic yet specific effects through interactions with an array of cellular proteins.

The aim of this collaborative and interdisciplinary POLYPHENOLPROT project is to fill this critical knowledge gap through the utilization of series of designed probes equipped with polyphenols of different structural classes and compatible with modern chemical proteomic techniques. The resulting “toolbox” will be put to use to fast-track the exploration of plant polyphenols as multi-target agents by identifying the full range of cellular proteins with which a given polyphenol interacts to induce favorable phenotypic responses.

In this context, POLYPHENOLPROT will notably focus on the utilization of some of these probes to evaluate the therapeutic potential of a novel anti-actin polyphenol, the C-glucosidic ellagitannin vescalagin, against osteoporosis, a degenerative bone disease that has today become a major public health problem because of a rapidly ageing world population, and because the drugs currently used induce deleterious secondary effects. The chemoproteomic applications of such polyphenol-equipped probes will enable us to elucidate the mode of binding of vescalagin to actin, to profile all proteins, besides actin, with which vescalagin interacts in bone-resorbing, as well as bone-forming cells, and to identify, through a systems biology-based analysis of the resulting proteome-wide data, the signaling/metabolic cellular pathways affected by the presence of this polyphenol. The same approach will be followed to revisit the bioactive potential of two structurally different well-known polyphenols, the grape stilbenoid resveratrol and the tea flavonoid epigallocatechin gallate.

The realization of POLYPHENOLPROT will rely on concerted and sustained efforts in synthetic organic chemistry, cell biology, proteomics and systems biology, and its success will permit to reach, for the first time, a holistic understanding of polyphenol bioactivities, and to establish the foundation of an exciting quest towards the development of novel polyphenol-based “multi-target” therapeutics.