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High Activity Mutants of Cocaine Esterase for Cocaine Hydrolysis Chang-Guo Zhan University of Kentucky, [email protected]

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High Activity Mutants of Cocaine Esterase for Cocaine Hydrolysis Chang-Guo Zhan University of Kentucky, Zhan@Uky.Edu University of Kentucky UKnowledge Pharmaceutical Sciences Faculty Patents Pharmaceutical Sciences 1-30-2018 High Activity Mutants of Cocaine Esterase for Cocaine Hydrolysis Chang-Guo Zhan University of Kentucky, [email protected] Fang Zheng University of Kentucky, [email protected] Lei Fang University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits oy u. Follow this and additional works at: https://uknowledge.uky.edu/ps_patents Part of the Pharmacy and Pharmaceutical Sciences Commons Recommended Citation Zhan, Chang-Guo; Zheng, Fang; and Fang, Lei, "High Activity Mutants of Cocaine Esterase for Cocaine Hydrolysis" (2018). Pharmaceutical Sciences Faculty Patents. 172. https://uknowledge.uky.edu/ps_patents/172 This Patent is brought to you for free and open access by the Pharmaceutical Sciences at UKnowledge. It has been accepted for inclusion in Pharmaceutical Sciences Faculty Patents by an authorized administrator of UKnowledge. For more information, please contact [email protected]. I IIIII IIIIIIII Ill lllll lllll US009879240B2lllll lllll lllll lllll lllll lllll 111111111111111111 c12) United States Patent (IO) Patent No.: US 9,879,240 B2 Zhan et al. (45) Date of Patent: Jan.30,2018 (54) HIGH ACTIVITY MUTANTS OF COCAINE Beadle, B. M., and Shoichet, B. K. (2002) Structural bases of ESTERASE FOR COCAINE HYDROLYSIS stability-function tradeoffs in enzymes. J. Mo!. Biol. 321, 285- 296. (71) Applicant: University of Kentucky Research Tokuriki, N., Stricher, F., Serrano, L., and Tawrik, D. S. (2008) How Foundation, Lexington, KY (US) protein stability and new functions trade off PLoS Comput. Biol. 4, el000002. (72) Inventors: Chang-Guo Zhan, Lexington, KY Thomas, V. L., McReynolds, A. C., and Shoichetb, B. K. (2010) (US); Fang Zheng, Lexington, KY Structural bases for stability-function tradeoffs in antibiotic resis­ (US); Lei Fang, Lexington, KY (US) tance. J. Mo!. Biol. 396, 47-59. Brim, R. L., Nance, M. R, Youngstrom, D. W., Narasimhan, D., (73) Assignee: University of Kentucky Research Zhan, C.-G., Tesmer, J. J., Sunahara, R. K., and Woods, J. H. (2010) A thermally stable form of bacterial cocaine esterase: A potential Foundation, Lexington, KY (US) therapeutic agent for treatment of cocaine abuse. Mo!. Pharmacol. 77, 593-600. ( *) Notice: Subject to any disclaimer, the term ofthis Collins, G. T., Brim, R. L., Narasimhan, D., Ko, M.-C., Sunahara, patent is extended or adjusted under 35 R. K., Zhan, C.-G., and Woods, J. H. (2009) Cocaine esterase U.S.C. 154(b) by 173 days. prevents cocaine-induced toxicity and the ongoing intravenous self-administration of cocaine in rats. J. Pharmacol. Exp. They. 331, (21) Appl. No.: 14/924,181 445-455. Narasimhan, D., Nance, M. R., Gao, D., Ko, M.-C., Macdonald, J., Tamburi, P., Yoon, D., Landry, D. M., Woods, J. H., Zhan, C.-G., (22) Filed: Oct. 27, 2015 Tesmer, J. J. G., and Sunahara, R K. (2010) Structural analysis of thermostabilizing mutations of cocaine esterase. Protein. Eng. Des. (65) Prior Publication Data Se!. 23, 537-547. Narasimhan, D., Collins, G. T., Nance, M. R., Nichols, J., Edwald, US 2016/0122732 Al May 5, 2016 E., Chan, J., Ko, M.-C., Woods, J. H., Tesmer, J. J. G., and Sunahara, R. K. (2011) Subunit stabilization and polyethylene glycolation of Related U.S. Application Data cocaine esterase improves in vivo residence time. Mo!. Pharmacal. (60) Provisional application No. 62/073,562, filed on Oct. 80, 1056-1065. 31, 2014. Collins, G. T., Zaks, M. E., Cunningham, A. R., St, Clair, C., Nichols, J., Narasimhan, D., Ko, M.-C., Sunahara, R. K., and Woods, J. H. (2011) Effects of a long-acting mutant bacterial (51) Int. Cl. cocaine esterase on acute cocaine toxicity in rats. Drug Alcohol A61K 38/00 (2006.01) Depend. 118, 158-165. C12N 9/18 (2006.01) Collins, G. T., Narasimhan, D., Cunningham, A. R., Zaks, M. E., A61K 38/46 (2006.01) Nichols, J., Ko, M.-C., Sunahara, R. K., and Woods, J. H. (2012) Longlasting effects of a PEGylated mutant cocaine esterase (CocE) (52) U.S. Cl. on the reinforcing and discriminative stimulus effects of cocaine in CPC .............. C12N 9/18 (2013.01); A61K 38/465 rats. Neuropsychopharmacology 37, 1092-1103. (2013.01); Cl2Y 301/01084 (2013.01) Collins, G. T., Brim, II L., Noon, K. R., Narasimhan, D., Lukacs, N. (58) Field of Classification Search W., Sunahara, R. K., Woods, J. H., and Ko, M.-C. (2012) Repeated CPC ........ A61K 38/00; A61K 38/465; C12N 9/18; administration of a mutant cocaine esterase: Effects on plasma cocaine levels, cocaine-induced cardiovascular activity, and C12Y 301/01084 immune responses in rhesus monkeys. J. Pharmacol. Exp. Ther. 342, See application file for complete search history. 205-213. Yang, W., Pan, Y., Zheng, F., Cho, H., Tai, H.-H., and Zhan, C.G. (56) References Cited (2009) Free-energy perturbation simulation on transition states and redesign of butyrylcholinesterase. Biophys. J. 96, 1931-1938. PUBLICATIONS (Continued) Carrera, M. R. A., Kaufmann, G. F., Mee, J. M., Meijler, M. M., Primary Examiner - Kagnew H Gebreyesus Koob, G. F., and Janda, K. D. (2004) Treating cocaine addiction (74) Attorney, Agent, or Firm - Stites & Harbison, with viruses. Proc. Natl. Acad. Sci. U.S.A. 101, 10416-10421. PLLC; Mandy Wilson Decker Meijler, M. M., Kaufmann, G. F., Q, L., Mee, J. M., Coyle, A. R., Moss, J. A., Wirsching, P., Matsushita, M., and Janda, K. D. (2005) (57) ABSTRACT Fluorescent cocaine probes: A tool forthe selection and engineering The Bacterial cocaine esterase (CocE) mutants disclosed of therapeutic antibodies. J. Am. Chem. Soc. 127, 2477-2484. Larsen, N. A., Turner, J. M., Stevens, J., Rosser, S. J., Basran, A., herein each have enhanced catalytic efficiency for ( -)­ Lerner, R. A., Bruce, N. C., and Wilson, I. A. (2002) Crystal cocaine, as compared to CocE mutants in the prior art, structure of a bacterial cocaine esterase. Nat. Struct. Mo!. Biol. 9, including CocE mutant E172-173. The presently-disclosed 17-21. subject matter further includes a pharmaceutical composi­ Ko, M.-C., Bowen, L .D., Narasimhan, D., Berlin, A. A., Lukacs, N. tion including a mutant of bacterial cocaine hydrolase, as W., Sunahara, R K., Cooper, Z. D., and Woods, J. H. (2007) Cocaine described herein, and a suitable pharmaceutical carrier. The esterase: Interactions with cocaine and immune responses in mice. presently-disclosed subject matter further includes a method J. Pharmacol. Exp. Ther. 320, 326-933. of treating a cocaine-induced condition comprising admin­ Gao, D., Narasimhan, D. L., Macdonald, J., Ko, M.-C., Landry, D. istering to an individual an effective amount of a mutant of W., Woods, J. H., Sunahara, R. K., and Zhan, C.-G. (2009) Thermostable variants of cocaine esterase for long-time protection bacterial cocaine hydrolase variant, as disclosed herein, to against cocaine toxicity. Mo!. Pharmacol. 75, 318-323. accelerate cocaine metabolism and produce biologically Shoichet, B. K., Baase, W. A., Kurold, R, and Matthews, B. W. inactive metabolites. ( 1995) A relationship between protein stability and protein function. Proc. Natl. Acad. Sci. U.S.A. 92, 452-456. 14 Claims, 5 Drawing Sheets US 9,879,240 B2 Page 2 (56) References Cited PUBLICATIONS Hou, S., Xue, L, Yang, W., Fang, L., Zheng, F., and Zhan, C.-G. (2013) Substrate selectivity of high-activity mutants of human butyrylcholinesterase. Org. BiotnoL Chem. 11, 7477-7485. Pan, Y., Gao, D., Yang, W., Cho, H., Yang, G., Tai, H.-H., and Zhan, C.-G. (2005) Computational redesign of human butyrylcholinesterase for anticocaine medication. Proc. Natl. Acad. Sci. U.S.A. 102, 16656-16661. Zheng, F., Yang, W., Xue, L., Hou, S., Liu, J., and Zhan, C.-G. (2010) Design of high-activity mutants of human butyrylcholinesterase against (--)-cocaine: structural and energetic factors affecting the catalytic efficiency. Biochemistry 49, 9113- 9119. Gao, D., and Zhan, C.-G. (2006) Modeling evolution of hydrogen bonding and stabilization of transition states in the process of cocaine hydrolysis catalyzed by human butyrylcholinesterase. Pro­ teins 62, 99-110. Hamza, A, Cho, H., Tai, H. H., and Zhan, C.-G. (2005) Molecular dynamics simulation of cocaine binding with human butyrylcholinesterase and its mutants. J. Phys. Chem. B 109, 4776- 4782. Pan, Y., Gao, D., Yang, W., Cho, H., and Zhan, C.-G. (2007) Free energy perturbation (FEP) simulation on the transition states of cocaine hydrolysis catalyzed by human butyrylcholinesterase and its mutants. J. Am. Chem. Soc. 129, 13537-13543. Zheng, F., Yang, W., Ko, M.-C., Liu, J., Cho, H., Gao, D., Tong, M., Tai, H.-H., Woods, J. H., and Zhan, C.-G. (2008) Most efficient cocaine hydrolase designed by virtual screening of transition states. J. Am. Chem. Soc. 130, 12148-12155. U.S. Patent Jan.30,2018 Sheet 1 of 5 US 9,879,240 B2 ··············· Lt96i:t,l.fdlb ··�·· ·.·.·.·.·.·.·.·.·.·.·.·.·.· lJOlh·tl�X.fa ,:,UUlhfliHHl(:;,··· , '* .,. ,·1·-·+ . : . UUt ,us:,l ·i FI(;S. 1A-1C U.S. Patent Jan.30,2018 Sheet 2 of 5 US 9,879,240 B2 (A) T·1: �-,n £ .£, $ .:+r-.l:'9}"Gl' . "'l'-:t>Q: .{ -�" - .• 40 80 -· (-}(:�tidth.>(tti\l) � l(l[t, (B) tf 4 °" �� y·1··.. •.. · .../;;;...:.',.R,r··1 ,:�,:, ./�.1Q''f'< f,��-.-t('_;J=-.:··._:.'S1· s.ihe· ..: �� '"!•·; � :+eit'­ -�),;--· *""'\:. -# � l 4(1 so ()·C*)talne (pld) -�· -� � ;;t. .£ '� Tl 72RlG173Q/Ll96C!1301 C ci:: l 4() sn (-.,-.(:ntidnt.(tti\i) FIG·S. 2A-2C U.S. Patent Jan.30,2018 Sheet 3 of 5 US 9,879,240 B2 :.W 40 60 Sft H){} Htl Time (daf) :FlG. 3 , .•. i�':!;f,/t> ... ··:{'.=·· FIG·S. 4A-4D U.S. Patent Jan.30,2018 Sheet 4 of 5 US 9,879,240 B2 � E196-JO! '*' PEGyfate<l Fl96-30! ,-.. IOU -}!.· 80 ,;.;, =· 6ft ;;,. ,m ..." ''°' zo -� 24 4.S 11 96 lW 144 Time (ht)urs) FIG.
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