BIOINVENU CORPORATION — Department of Health and Human Services SBIR Phase I: NIDA

Description

Specific AimValidate the MORLinkLight assay with a pilot HTS to identify molecules modulating MOR traffickingSignificanceThe current crisis of opioid use disordersOUDsand opioid overdose deaths in the United States urgently demands safer and better therapeuticsTo develop better and safer therapeutic agents for the treatment of OUDsfirst and foremost is to have new bioassays which are different from the current approaches and are physiologically relevant to the underlying neurobiology of opioid addiction and chronic painand to use the bioassays to screen and identify new therapeutic leads for OUD drug developmentWe have developed MORLinkLight assayWe found thatproteins participate in GPCR trafficking and recyclingMORassociation signals can be promoted by MOR antagonists naloxonelive saving overdose drugand naltrexoneanti addiction drugMOR endomorphins can disrupt MORinteraction signalswhile at the same time promote MORarrestin interactionMORendocytosis and trafficking play a critical role in the development of opioid tolerance and dependenceThusthe MORLinkLight bioassay represents an unprecedented opportunity for screen and identification of new therapeutic agents for the treatment of OUDsExperimental DesignTaskConduct a pilot screen of small molecules modulating MORinteraction signalsWe plan to screen approximate totalsmall molecule libraries including approved drug libraryclinic compound libraryGPCR compound libraryand bioactive compound libraryTaskCharacterize positive hits identified from the screen for G protein andarrestin pathwaysMORis a new pathway assayThe hits identified by MORLinkLight assay may have different properties for G protein andarrestin signaling pathwaysWe will classify agonists and antagonists based on G protein signaling assayWe have developed MORarrestin LinkLight assay and the assay will be used to evaluate the hits forarrestin pathway activityBased on the three pathway assayswe expect to find multi pathway biased ligandsThese multi pathway biased ligands will enhance our understanding neurobiology of opioid addiction and chronic painas well as lead us to develop better and safer drugsNext Phase PlanThe phase I project will test the feasibility of this novel mechanism based approach for screening and identifying new molecules for OUDsOnce we demonstrate feasibilitya phase II plan that includes screening larger compound collectionsevaluating positive hits for DMPK studies in animalsand evaluating positive hits for animal models of paintolerancewithdrawaland addictionand in potential collaboration with NCATS will be proposedWe will partner the project with appropriate pharmaceutical companies to accelerate development when possibleSummaryAccumulating evidence suggests that opioid receptor desensitization and trafficking mechanisms are intimately connected to tolerance and addictionWe have developed a novel MORLinkLight assayWe foundproteins involved in MOR traffickingThusthe MORassay can be utilized for screening molecules modulating MOR traffickingThe potential hits identified from the proposed screen could have potentials for therapeutic agent development This SBIR phase I proposal is to validate newly developed MORbioassay in a pilot highthroughputHTSscreen and to characterize the hits identified from the screen for potential multi pathway biased ligandsVery recentlywe have developed MORbioassayThe assay can be used to monitor MOR trafficking which is linked to opioid actionsThusthe MORLinkLight assay represents an unprecedented opportunity and a new pathway approach to screen and identify potential therapeutic agents for the treatment of OUDs