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WO 2018/075670 Al 26 April 2018 (26.04.2018) W !P O PCT

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WO 2018/075670 Al 26 April 2018 (26.04.2018) W !P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/075670 Al 26 April 2018 (26.04.2018) W !P O PCT (51) International Patent Classification: (74) Agent: ROBINSON, Kathleen et al; Wilson Sonsini C12N 9/10 (2006.01) C12P 13/22 (2006.01) Goodrich & Rosati, 650 Page Mill Road, Palo Alto, CA C12N 15/52 (2006 .0 1) C12P 17/12 (2006 .0 1) 94304-1050 (US). C12N 15/63 (2006.01) C12P 17/18 (2006.01) (81) Designated States (unless otherwise indicated, for every CI2N 15/81 (2006.01) kind of national protection available): AE, AG, AL, AM, (21) International Application Number: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, PCT/US2017/057237 CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (22) International Filing Date: HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, 18 October 2017 (18.10.2017) KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (25) Filing Language: English MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (26) Publication Language: English SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (30) Priority Data: TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 18 October 2016 (18.10.2016) 62/409,837 (84) Designated States (unless otherwise indicated, for every 62/473,215 17 March 2017 (17.03.2017) kind of regional protection available): ARIPO (BW, GH, (71) Applicant: ANTHEIA, INC. [US/US]; 1505 O'Brien GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, Dirve, Suite Bl, Menlo Park, CA 94025 (US). UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (72) Inventors: SMOLKE, Christina, D.; 228 University Dri EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, ve, Menlo Park, CA 94025 (US). THODEY, Catherine; MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 181 Ada Avenue, #14, Mountain View, CA 94043 (US). TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, TRENCHARD, Isis; 376 Northumberland Avenue, Red KM, ML, MR, NE, SN, TD, TG). wood City, CA 9406 1 (US). (54) Title: METHODS OF PRODUCING NOR-OPIOID AND NAL-OPIOID BENZYLISOQUINOLINE ALKALOIDS (57) Abstract: A method of demethylizing an opioid to a nor-opioid is provided. Example reaction scheme: The method comprises contacting an opioid with at least one enzyme. Contact ing the opioid with the at least one enzyme converts the opioid to a nor-opioid. A method of converting a nor-opioid to a nal-opioid is provided. The method comprises contacting a nor-opioid with at least one enzyme. Contacting the nor- opioid with the at least one enzyme converts the nor-opioid to a nal-opioid. I © 00 o Figure 26 o [Continued on nextpage] WO 2018/075670 Al llll II II 11III II I II III I II II II III II I II Published: — with international search report (Art. 21(3)) — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) METHODS OF PRODUCING NOR-OPIOID AND NAL-OPIOID BENZYLISOQUINOLINE ALKALOIDS CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Application No. 62/409,837, filed October 18, 2016, and U.S. Provisional Application No. 62/473,215, filed March 17, 2017, which applications are incorporated herein by reference. BACKGROUND OF THE INVENTION [0002] Medicinal opioids are used for treating moderate to severe pain, but may exhibit addictive properties. Due to the mechanism by which medicinal opioids relieve pain, these medications are among the most effective painkillers in modern medicine. Additionally, however, medicinal opioids are also widely abused. In addressing the use of medicinal opioids, policy makers are tasked with balancing the under-treatment of pain, while mitigating the risk for opioid abuse. Pharmacotherapies have proven effective in treating and preventing opioid addiction but the high cost of these therapeutics is a limiting factor in the scope and reach of treatment programs. SUMMARY OF THE INVENTION [0003] The present disclosure provides methods for demethylating a first opioid to a second opioid. The present disclosure further provides methods for demethylating an opioid to a nor- opioid. Additionally, the present disclosure provides methods for altering an opioid to a nal- opioid. Further, the present disclosure provides engineered cells for producing a nor-opioid from an opioid present within the engineered cell. The present disclosure also provides engineered cells for producing a nal-opioid from a nor-opioid present within the engineered cell. [0004] An aspect of the invention provides a method for demethylating a first opioid to a second opioid. The method comprises contacting the first opioid with at least one enzyme, wherein contacting the first opioid with the at least one enzyme converts the first opioid to a second opioid through loss of an O-linked methyl group, wherein the first opioid is not selected from the group consisting of codeine and thebaine. [0005] Another aspect of the invention provides a method of demethylating an opioid to a nor- opioid. The method comprises contacting the first opioid with at least one enzyme, wherein contacting the first opioid with the at least one enzyme converts the first opioid to a second opioid through loss of an O-linked methyl group. The method also comprises contacting the second opioid with at least one enzyme, wherein contacting the opioid with the at least one enzyme converts the second opioid to a nor-opioid through loss of an N-linked methyl group. [0006] An additional aspect of the invention provides another method of demethylating an opioid to a nor-opioid. The method comprises contacting the opioid with at least one enzyme, wherein contacting the opioid with the at least one enzyme converts the opioid to a nor-opioid through removal of an N-linked methyl group from the opioid, wherein the opioid is not thebaine when the opioid contacts the at least one enzyme in vitro. [0007] A further aspect of the invention provides a method of altering an opioid to a nal-opioid. The method comprises contacting the opioid with at least a first enzyme, wherein contacting the opioid with the at least a first enzyme converts the opioid to a nor-opioid through removal of an N-linked methyl group from the opioid. The method also comprises contacting the nor-opioid with at least a second enzyme, wherein contacting the nor-opioid with the at least a second enzyme in the presence of a cofactor converts the nor-opioid to a nal-opioid through transfer of a sidechain from the cofactor. [0008] Another aspect of the invention provides another method of altering an opioid to a nal- opioid. The method comprises contacting the first opioid with at least one enzyme, wherein contacting the first opioid with the at least one enzyme converts the first opioid to a second opioid through loss of an O-linked methyl group. The method also comprises contacting the second opioid with at least a second enzyme, wherein contacting the opioid with the at least a second enzyme converts the second opioid to a nor-opioid through loss of an N-linked methyl group. Additionally, the method comprises contacting the nor-opioid with at least a third enzyme, wherein contacting the nor-opioid with the at least a third enzyme in the presence of a cofactor converts the nor-opioid to a nal-opioid through transfer of a sidechain from the cofactor. [0009] An additional aspect of the invention provides an engineered cell that produces a nor- opioid from an opioid present within the engineered cell, the engineered cell comprising a heterologous coding sequence encoding an N-demethylase produced by the engineered cell, wherein the N-demethylase converts the opioid within the engineered cell to the nor-opioid and wherein the nor-opioid is produced within the engineered cell. [0010] A further aspect of the invention provides an engineered cell that produces a nal-opioid from a nor-opioid present within the engineered cell, the engineered cell comprising a heterologous coding sequence encoding an N-methyltransferase produced by the engineered cell, wherein the N-methyltransferase converts the nor-opioid within the engineered cell to the nal- opioid. INCORPORATION BY REFERENCE [0011] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS [0012] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: [0013] FIG. 1 illustrates examples of synthesis, recycling, and salvage pathways of tetrahydrobiopterin, in accordance with embodiments of the invention. [0014] FIG. 2 illustrates a biosynthetic scheme for conversion of glucose to 4-HPA, dopamine, and 3,4-DHPA, in accordance with embodiments of the invention.
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