Medicinal opioids are essential medicines for treating pain, but exhibit addictive properties. The United States has committed significant resources to curb opioid dependence and overdose. The nal-opioids, a suite of antagonist and mixed partial agonist opioids, are an important group of pharmacotherapies used in drug- addicted patients for treating overdose, managing symptoms during detoxification, and maintenance by blocking reward responses. In pain management patients, nal-opioids are used in combination with opioids to prevent addiction and abuse, and to reduce side effects. Current production methods for nal-opioids are inefficient, expensive, and rely on the farming of a drug crop. The raw starting materials for nal-opioid synthesis are natural opiates that are extracted from opium poppy and subsequently chemically modified through a series of inefficient reaction steps. As a result of the costs associated with this process, nal-opioids command a substantially higher price than opiates that have not been chemically modified. For example, natural morphine active pharmaceutical ingredient (API) retails for ~$1,000/kg, whereas naloxone and buprenorphine cost ~$12,000/kg and ~$28,000/kg, respectively. Antheias technology will produce nal-opioids efficiently and at a fraction of the cost of the current production methods. The novel technology allows for total biosynthesis of nal-opioids by yeast fermentation, thereby removing the reliance on drug crop farming and changing the way these life-saving therapeutics are manufactured. Antheia will leverage its existing technology for producing opioids in yeast and extend the biosynthetic capabilities of these strains to include precursors of the nal-opioids, and ultimately the end products naloxone, naltrexone, and buprenorphine. Technoeconomic models indicate that Antheias unique technology will result in greater than a 10-fold reduction in the cost of producing these compounds. The objective of this Phase I SBIR project will be to develop engineered yeast strains that produce high levels of noroxymorphone, the direct precursor for the nal-opioids naloxone and naltrexone, through whole cell biocatalysis. First, a yeast strain capable of high-level oxycodone biosynthesis will be constructed by the addition and optimization of two enzymatic steps to Antheias existing opioid production strains. Second, two novel O-demethylase and N-demethylase enzyme activities will be developed with enzyme evolution and a high-throughput colorimetric screening assay. Finally, the O- and N-demethylase activities will be combined with the optimized oxycodone-producing strain to deliver a novel bioproduction system for noroxymorphone. This project will address major technical barriers to the microbial production of nal-opioids and support the commercial viability of this technology. By addressing much of the technical risk, this SBIR project will enable investor-funded development and scale up, and Antheias entry into a new product line to help combat growing opioid abuse and addiction.
Public Health Relevance Statement: Narrative Nal-opioids, such as naloxone, naltrexone and buprenorphine, are pharmacotherapies that save and rebuild lives by treating chemical dependence on opioids. However, these active pharmaceutical ingredients demand a premium price due to their complex production process in which molecules extracted from opium poppy are tailored to exhibit antagonist properties. Antheias unique microbial production technology will dramatically decrease the price of producing nal-opioids and provide a secure, sustained supply for drug addiction treatment.
Project Terms: abstracting; addiction; Address; Adverse effects; Agonist; Anabolism; Biological Assay; Buprenorphine; catalyst; Cells; Chemicals; Codon Nucleotides; combat; Complex; cost; Cytochrome P450; design; Development; drug addict; Drug Addiction; Drug Metabolic Detoxication; Emergency Situation; Engineering; Ensure; enzyme activity; enzyme pathway; Enzymes; Epidemic; Evolution; Excision; Exhibits; Farming environment; Fermentation; functional group; Funding; Housing; Intellectual Property; Libraries; Life; Link; Maintenance; Medicine; Methods; methyl group; microbial; microbial host; Modeling; Modification; Morphine; Mutagenesis; Naloxone; Naltrexone; Narcotic Antagonists; new technology; Nitrogen; novel; O-Demethylating Oxidoreductases; Opiate Addiction; Opiates; Opioid; opioid abuse; Opioid Analgesics; opioid use; opioid withdrawal; Opium; Overdose; Oxycodone; Oxymorphone; Pain; Pain management; Papaver; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; Plants; prevent; Price; Process; Production; promoter; Property; Reaction; Reagent; Recovery; Research; Resources; response; Rewards; Risk; scaffold; scale up; screening; Secure; Series; Side; Small Business Innovation Research Grant; Specificity; symptom management; synthetic biology; System; Techniques; Technology; Thebaine; Therapeutic; Time; Titrations; United States; Variant; Work; Yeasts
