CE44 - Biochimie du Vivant

Exploring Probes & Inhibitors Designed to Engage hsTY: a Route to Melanogenesis In vivo Suppression – EPIDERMIS

Submission summary

Human tyrosinase (hsTY) is a metalloenzyme involved in the synthesis of the main skin pigments, melanins, and especially in the two key steps of this biosynthetic pathway: the successive oxidations of L-tyrosine and L-DOPA. An uncontrolled production of melanins is associated with several pathologies, such as various hyperpigmentation-based diseases, and with the emergence of melanoma resistance to conventional anticancer therapies. The inhibition of tyrosinase is a well-established strategy for controlling melanin production in vivo, but almost all reported bioactive compounds were designed using non-relevant models such as mushroom tyrosinase, a readily commercially available enzyme that has only low homology with hsTY, and that displayed significantly different interaction patterns with inhibitors and substrates. Thus, almost all skin-whitening agents used worldwide, such as kojic acid, have shown very weak activities against hsTY, and are used in high concentrations in human-directed dermocosmetic applications, thereby leading to nocive adverse effects and carcinogenicity. By taking advantage of recent advances in hsTY structure knowledge and of novel large-scale hsTY production protocols, we propose to rely on the aurone scaffold, which has already demonstrated its potential against hsTY (one derivative is one of the most active inhibitors of the enzyme reported to date), for rationally conceiving new selective agents, active in a cellular context and in a preclinical assay, by getting rid of irrelevant tests in non-human medium. In addition, preliminary works already showcased the aurone scaffold as a promising platform for the development of fluorogenic probes for biomolecules. The, the use of fine-tuned analogues will allow a specific detection of hsTY in biological medium, by relying on a strategy of fluorescence “turn-on” upon contact with the target. The detection will be based on the specific structure of the protein, and not its catalytic activity, as it is the case for the totality of already reported tyrosinase probes, raising interference issues especially with ROS (Reactive Oxygen Species) and activity-related enzymes (e.g. tyrosine hydroxylase). Thus, these innovative biosensors will potentially lead to more accurate and reliable analytical tools for human-directed use, e.g. for the specific detection of hsTY in melanoma or Parkinson’s disease contexts.

Project coordination

Romain Haudecoeur (DEPARTEMENT DE PHARMACOCHIMIE MOLECULAIRE)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

DPM DEPARTEMENT DE PHARMACOCHIMIE MOLECULAIRE

Help of the ANR 184,960 euros
Beginning and duration of the scientific project: September 2019 - 48 Months

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