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Publication Number
US-11560578-B2
Publication Date
2023-01-24
Expiration Date
Abstract
Disclosed are methods for converting a first morphinan alkaloid compound into a second morphinan alkaloid compound in the presence of a neopinone isomerase enzyme under reaction conditions permitting the conversion of the first alkaloid compound into the second alkaloid compound. The first alkaloid compound can be neopinone or neomorphinone. The second alkaloid compound can be codeinone or morphinone. Related compositions are also disclosed.
Core Innovation
The invention provides a method of making a second morphinan compound by using a host cell transformed with an expression construct comprising a nucleic acid sequence encoding neopinone isomerase. Neopinone isomerase is expressed with a first morphinan compound under reaction conditions permitting conversion of the first morphinan compound into the second morphinan compound.
The first and second morphinan compounds are specified by morphinan structures and chemical structures (I) and (II), including embodiments in which a tetrahydrofuranyl ring is formed by a bridging oxygen between C4 and C5. The second morphinan compound has a saturated carbon bond at position C8-C14 and a mono-unsaturated carbon bond at position C7-C8, and R1 is hydroxyl or methoxy for the morphinan compounds used in the conversion.
The disclosure also describes morphinan biosynthesis workflow embodiments with additional named enzymes including codeinone reductase, codeine-O-demethylase, and morphinone reductase B. These embodiments produce further morphinan compounds such as neopinone, codeinone, codeine, neomorphinone, morphinone, morphine, and neopine, and include embodiments related to isolation of morphinan compounds and quantitative limits for byproduct compounds.
Claims Coverage
The document includes one independent claim directed to neopinone isomerase-mediated bioconversion in a transformed host cell. Dependent claims refine the inventive concept by constraining morphinan structural features, defining specific chemical structures and substituent R1, adding additional enzymatic conversion steps, and imposing isolation and byproduct quantitative limits.
Neopinone isomerase-expressing host cell conversion
A method of making a second morphinan compound, comprising providing a host cell transformed with an expression construct encoding neopinone isomerase and expressing neopinone isomerase with a first morphinan compound to convert the first morphinan compound into the second morphinan compound under reaction conditions, wherein the second morphinan compound has a saturated carbon bond at position C8-C14 and a mono-unsaturated carbon bond at position C7-C8.
Neopinone isomerase sequence-defined by SEQ ID NO sets
The neopinone isomerase is defined as a polypeptide or nucleic acid molecule comprising SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, and SEQ ID NO: 21, including nucleic acid and polypeptide identity thresholds and genetic-code degeneration options.
Specified morphinan structure and substituent options
Embodiments where the first and second morphinan compounds include a tetrahydrofuranyl ring formed by a bridging oxygen between C4 and C5, and where R1 is hydroxyl or methoxy.
Additional enzymatic conversion steps
Embodiments adding further conversions by expressing additional named enzymes, including codeinone reductase, codeine-O-demethylase, and morphinone reductase B, to produce further morphinan compounds such as neopinone, codeinone, codeine, neomorphinone, morphinone, morphine, and neopine.
Isolation of morphinan compounds and byproduct quantitative limits
Embodiments that include isolating a morphinan compound and imposing quantitative limits on a byproduct compound, including neopine as a fraction of total morphinan compounds.
The claim coverage is anchored in converting a first morphinan into a second morphinan using host-cell-expressed neopinone isomerase with specified sequence features, producing a second morphinan with defined C7-C8 and C8-C14 bond saturation and unsaturation. Dependent refinements add tetrahydrofuranyl ring and chemical-structure constraints, additional named enzymatic conversion steps, isolation of intermediates, and quantitative byproduct constraints.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating a patient by administering a composition containing a morphinan prepared according to the disclosed methods.
Using morphinan compounds as precursors or feedstock for derivative morphinans, including conversion examples involving codeinone to codeine to morphine and morphinone to morphine.
Pharmaceutical formulation as pharmaceutical compositions including vehicles, excipients, and pharmaceutically acceptable salts, with oral or intravenous administration described.
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