The purpose of this Funding Opportunity Announcement (FOA) is to support research projects focusing on the identification of druggable new targets and discovery of optimizable probes for development of safe and efficacious medications to prevent and treat opioid use disorders (OUDs), opioid overdose, and opioid-polysubstance use comorbidities. This FOA is part of the NIH Helping to End Addictions Long-term (HEAL) initiative to accelerate the development of novel medications to treat all aspects of the opioid addiction cycle, including progression to chronic use, withdrawal symptoms, craving, relapse, and overdose.
There is an ongoing opioid use and overdose crisis in the United States. Opioids that are often prescribed for the treatment of pain can lead to opioid misuse and Opioid Use Disorders (OUDs). It has been reported that more than 3 million Americans have OUDs, and many started their addiction with prescribed opioids. One of the most devastating consequences of opioid misuse is opioid overdose, which can produce respiratory depression and death. Drug overdose is a leading cause of accidental death in the US, with an estimated 50,000 opioid-involved overdose deaths in 2019. Although safe and effective pharmacotherapies for the treatment of opioid use disorders and for the prevention or reversal of opioid overdose are available, there are limitations to their use, and they are underutilized. For example, methadone and buprenorphine are opioid agonist therapies and, as such, have policy restrictions on their use in treating OUD. The opioid antagonist naloxone is not optimally effective for reversal of overdoses of highly potent opioids such as fentanyl. Therefore, there is an urgent need to develop new medications through the identification of novel targets and lead molecules to enable the development of new therapeutic approaches that will be effective at various stages along the trajectory of OUD from initiation to chronic use, physical dependence, relapse, and overdose.
Recent research using new technologies has advanced our knowledge of how opioids produce their many effects from the molecular to circuit level analysis. A variety of methods have been developed as enabling techniques to interrogate signaling pathways and to identify/validate druggable targets of interest. These include single-cell multiomics, high-throughput chemotranscriptomics, genetically encoded biosensors, CRISPR-based approaches, targeted protein degradation, click chemistry, and use of genetically modified organisms and animal models. The application of these emerging technologies along with nonbiased approaches provides an opportunity to identify novel targets encompassing enzymes, receptors, ion channels, intracellular trafficking, neuropeptides, signaling pathways and networks, protein-protein interactions, genetic and epigenetic targets, or other biological mechanisms of relevance to OUDs and opioid overdose.
Parallel advances in drug development technologies such as the ability to screen large synthetically accessible or available libraries of compounds including, DNA encoded libraries, virtual screening of ultra-large libraries of molecules and application of computational tools, machine learning methods, and artificial intelligence have the potential to shorten the time needed for identifying probe molecules for interrogating the targets as well as for optimization of the probes and lead molecules toward the drug development path. The developments in target identification coupled with the advances in ligand discovery/optimization approaches provide an unprecedented opportunity to accelerate the development of drugs for treatment of OUDs and opioid overdose. The purpose of this FOA is to support such studies leading to the identification of druggable new targets and discovery of optimizable probes for development of safe and efficacious medications to prevent and treat OUDs and opioid overdose.
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Filed Under: Funding Opportunities