Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY/ABSTRACT Opioid abuse has become a growing epidemic in the US, causing tens of thousands of overdose deaths every year especially because of fentanyl-related opioids. Fentanyl is a synthetic opioid that acts as an agonist on the μ-opioid receptors at various sites and is estimated to be 100 times more potent than morphine. This has led to the classification of potent synthetic opioids as Pharmaceutical Based Agents (PBAs) that could be used as a potential offensive chemical weapon, indicating the critical need for effective medical countermeasures (MCMs). Naloxone is a non-selective competitive opioid receptor antagonist that is given to reverse the symptoms of opioid overdose or toxicity. It is highly effective, but also has several disadvantages. For example, it has low efficacy against potent opioids like fentanyl and can require multiple doses to avoid renarcotization, but may then precipitate opioid-withdrawal syndrome. Bioscavengers are an attractive MCM strategy for both post-exposure therapy and prophylaxis against toxic agents such as organophosphate nerve agents. Recently, monoclonal antibodies (mAbs) were shown in mice to be fentanyl and carfentanil bioscavengers, and to reduce blood opioid concentrations. However, since a stoichiometric bioscavenger is needed to neutralize the fentanyl molecules, and since mAbs are large (~150 kDa), the dose of the mAbs required for protection from or treatment of opioid toxicity is large and difficult to administer. Therefore, an urgent need exists for new MCMs that can be used in conjunction with receptor antagonists like naloxone to overcome the limitations of current treatments. This exploratory research program seeks to develop synthetic scavengers for fentanyl for opioid overdose and toxicity reversal utilizing SRI’s proprietary Fiber-optic Array Screening Technology (FAST) and protein-like synthetic molecules (Techneins). We developed this platform to enable the design, synthesis, screening and sequencing of large combinatorial “one-bead one-compound” Technein libraries. FAST enables screening against multiple targets in complex biological matrices to yield lead compounds with specific biological functionality and high selectivity. This approach has been validated as a drug discovery tool for inhibitors of protein-protein interactions and for small molecule binders. In preliminary studies, when a small portion of a library was screened against fentanyl, several Technein hits were identified and confirmed to bind. Their relatively small size (4-6 kDa), high stability, lack of immunogenicity and a good terminal half-life (~22 hours), make Techneins ideal candidates as opioid scavengers. Here we aim to develop synthetic scavenger Techneins for fentanyl and test and optimize their ability to block fentanyl activity in functional cellular assays (Aim 1) and provide basic PK and pre-clinical efficacy data for the top anti-fentanyl lead (Aim 2). These studies will enable new avenues for the development of efficacious MCMs against fentanyl and related synthetic opioids, as well as paving the way for coping with other types of toxic agents. Moreover, the project may further demonstrate utility of an innovative new drug discovery platform.
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