A preclinical drug candidate targeting angiotensin 2 receptor 2 (AT2R) pathways for the treatment of pain – MyPainkiller

The current therapeutic options for chronic pain are limited and often come with significant side effects, including the potential for addiction. To address this challenge, the MyPainkiller project focuses on harnessing a natural product derived from actinomycetes, known as mycolactone, which has demonstrated potent long-acting pain-relieving properties at doses one thousand lower than morphine in rodents. Advantageously, mycolactone does not impede motricity. By formulating mycolactone into poly-cyclodextrin-based nanoparticles (referred to as pCD-ML), we have dramatically improved its physicochemical properties, positioning it as a promising drug candidate for pain management.
This innovative product, recently patented by our institutions (INSERM / CNRS), marks the culmination of collaborative efforts among four multidisciplinary teams over the past decade: IPL (Institut Pasteur de Lille), ISMO (Institut de Sciences Moléculaires d’Orsay), INCIT (Immunologie et Nouveaux Concepts en Immunothérapie, Nantes), and IGF (Institut de Génomique Fonctionnelle, CNRS, Montpellier).
Building on this strong foundation, our project aims to address key gaps in mycolactone's development. Firstly, we will focus on assessing the long-term stability of pCD-ML formulation, its tissue diffusion, and early ADME (absorption, distribution, metabolism, and excretion) characteristics. Advanced techniques, such as MALDI-MS imaging and 13C-labeling of mycolactone, will be employed to investigate tissue diffusion and to detect metabolites.
Secondly, we will decipher the mechanisms by which the pCD carrier potentiates the mycolactone analgesic properties. Given recent research on the involvement of AT2R (Angiotensin II Receptor Type 2) in mycolactone's effects, we will delve into its engagement at the cellular and subcellular levels. This entails deciphering the signaling pathways involved in mycolactone's action within neurons, macrophages, and their interplay, leveraging innovative technologies like APEX for intracellular signaling analysis and primary macrophage-neuron co-cultures coupled with image-based analysis.
Finally, we will evaluate the efficacy of the pCD-ML formulation in three mouse models of peripheral pain, building upon previous experiments with mycolactone alone.
This collaborative effort represents an opportunity to bridge complementary expertise and overcome barriers together. MyPainkiller project aims to meet the urgent societal need for effective pain management and to provide solid foundation for the establishment of a public-private partnership for further preclinical development of the product.