DS04 - Vie, santé et bien-être

Deciphering molecular and cellular pathways in pain control: nature as inspiration for the rational design of new potent analgesics – AT2R-TRAAK-BIOANALGESICS

Submission summary

Understanding pain, and relieving its symptoms, represent crucial challenges on scientific and medical grounds, with the available panoply of analgesics largely insufficient. Notably to remedy this situation, we have witnessed recently a marked interest in the analgesic solutions elaborated by mother nature (Results in Analgesia-Darwin 1, Pharma 0" NEJM, 2013). The present project builds on one such natural system uncovered by members of the consortium (Marion et al. Cell 2014), elucidating the causes of painlessness in Buruli ulcer disease. In this disease the severe skin ulcerations caused by Mycobacterium ulcerans, the etiological agent of the disease, are painless. Painlessness was attributed to nerve destruction, caused by the toxin mycolactone secreted by the bacterium. We showed that such is not the case, but rather mycolactone exerts an analgesic effect, triggering cellular hyperpolarization upon binding to the angiotensin II receptor (AT2R), leading to the activation of potassium channels, of the TRAAK-type.
The central aim of the project is the development of new potent analgesics, building on the detailed elucidation of the AT2R- TRAAK model. To reach this aim the project deploys a full-spectrum approach, from detailed molecular and cellular characterizations, to extensive exploratory screenings of natural compounds and in vivo pain assessments. The project is characterized by several promising strengths, as well as notable safeguards relative to the risks inherent to such approaches:
1) The effect of mycolactone appears to be very long lasting, thus comparing very favourably to compounds such as morphine, with the short duration of action being recognized as a severe shortcoming.
2) The system under study appears to be significantly more complex than other bioinspirational models for analgesia (for example scorpion toxins acting directly on ion channels), making the study more difficult, but offering from the applications perspective many different handles to interfere with the system.
3) In various traditional medicines aiming to alleviate pain the active compound appears to belong to the generic family of lactones. This observation provides then a natural path for the extension of the studies to the discovery of other compounds acting on the AT2R-TRAAK system, through extensive screenings of lactone products.
4) The scientific approach adopted provides a sound safeguard relative to the medical objectives of the project, as the expected informations concerning the poorly characterized AT2R GPCR receptor and the TRAAK ionic channel will be valuable for their own sakes, notably in view of the increasing appreciation of the physiological importance of these components.
In this background, the project is organized following 4 tasks:
1) Pathway elucidations: The detailed study of the system at the level of the TRAAK "output" will allow to identify and characterise the mechanisms responsible of the blocking, or delaying, of the desensitization of the channel, a feature which could account for the long duration effect of mycolactone. We will try to identify the domain(s) of TRAAK specifically involved in the analgesia phenomenon induced by (myco)lactones/ AT2R. We shall characterise the spatial organisation, at the level of the membrane, of the various partners involved in the signal transduction;
2) Pharmacological focus on AT2R. The detailed analysis of the ligands capable of binding to AT2R, triggering the TRAAK channels, will allow a refined characterisation of the specific domains of AT2R receptors involved in the analgesia mediated by the (myco)lactones;
3) Screening explorations: A high-throughput screening of compounds from various collections of chemical libraries, concerning natural lactones and derivatives of such molecules, will be implemented;
4) In vivo assessments: The analgesic effect of the various promising candidates in the analyses and explorations above will be tested on in vivo pain models.

Project coordination

Priscille BRODIN (INSTITUT PASTEUR DE LILLE)

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

IPL INSTITUT PASTEUR DE LILLE
CRCINA Centre de Recherche en Cancérologie et immunologie Nantes - Angers
Institut de génomique fonctionnelle
iBV Institut de biologie de Valrose
ISCR Institut des Sciences Chimiques de Rennes
IPP INSTITUT PASTEUR (BP)

Help of the ANR 813,181 euros
Beginning and duration of the scientific project: - 48 Months

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