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WO 2013/059622 Al 25 April 2013 (25.04.2013) (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 2013/059622 Al 25 April 2013 (25.04.2013) (51) International Patent Classification: Cambridge, MA 02138 (US). UNNIKRISHNAN, Meera A61K 38/00 (2006.01) C07K 2/00 (2006.01) [IN/IT]; Via Quinto Settano, 35, 1-53 100 Sienna (IT). C12Q 1/00 (2006.01) (74) Agents: RESNICK, David S. et al; Nixon Peabody LLP, (21) International Application Number: 100 Summer Street, Boston, MA 021 10-213 1 (US). PCT/US20 12/06 1066 (81) Designated States (unless otherwise indicated, for every (22) International Filing Date: kind of national protection available): AE, AG, AL, AM, 19 October 2012 (19.10.2012) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (25) Filing Language: English DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (26) Publication Language: English HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (30) Priority Data: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 61/548,983 October 201 1 ( I .10.201 1) US NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, 61/588,421 1 January 20 12 ( I .01.2012) US RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, (71) Applicant: PRESIDENT AND FELLOWS OF HAR¬ TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, VARD COLLEGE [US/US]; 17 Quincy Street, Cam ZM, ZW. bridge, MA 02138 (US). (84) Designated States (unless otherwise indicated, for every (72) Inventors; and kind of regional protection available): ARIPO (BW, GH, (71) Applicants : KANDROR, Olga [US/US]; 2 1 Wallace St., GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, Newton, MA 02461 (US). GOLDBERG, Alfred, Lewis UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, [US/US]; 20 Chapel St., Apt. 1010, Brookline, MA 02446 TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (US). AKOPIAN, Tatos [US/US]; 58 Johnson Street, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, West Roxbury, MA 02132 (US). RUBIN, Eric, J. MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, [US/US]; 283 Woodward Street, Waban, MA 02468 (US). TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, RAJU, Ravikiran, M. [US/US]; 472 Adams Mail Center, ML, MR, NE, SN, TD, TG). [Continued on nextpage] (54) Title: TREATMENTS FOR MYCOBACTERIUM TUBERCULOSIS © (57) Abstract: The technology described herein relates to treatments for tuberculosis which target the ClpPlP2 protease complex, in o cluding ClpCl. Further embodiments relate to assays and screens for modulators of the ClpPlP2 protease complex, including ClpCl. w o 2013/059622 A i llll II II 11III III III 111II I II IIII II I II Declarations under Rule 4.17: Published: — as to applicant's entitlement to apply for and be granted — with international search report (Art. 21(3)) a patent (Rule 4.1 7(H)) — with sequence listing part of description (Rule 5.2(a)) — as to the applicant's entitlement to claim the priority of the earlier application (Rule 4.17(Hi)) TREATMENTS FOR MYCOBACTERIUM TUBERCULOSIS Field of Invention [0001] The invention relates to methods of treating Mycobacterium tuberculosis infections. Government Support [0002] This invention was made in part with U.S. Government support from grants GM51923-13 and R21NS067598 from the National Institutes of Health and grant 5RO1A1071881-02 from the National Institute of Allergy and Infectious Diseases. The U.S. Government has certain rights in this invention. Sequence Listing [0003] The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on October 19, 2012, is named 28670072.txt and is 26,915 bytes in size. Background [0004] Tuberculosis is a devastating disease that affects worldwide about 100 million people and causes nearly 2 million deaths annually, making it one of leading causes of infectious disease mortality. It has been estimated that a third of all humans are infected with latent Mycobacterium tuberculosis (Mtb). Moreover, Mtb has become increasingly resistant to available antibiotics. Therefore, identifying new targets for drug development (i.e. enzymes that are essential for viability of Mtb) and developing selective inhibitors of their function is critical if we are to conquer this devastating disease. Ideal targets for drug development should be enzymes essential for bacterial viability that differ in physicochemical properties and specificity from those present in humans. Summary of Invention [0005] The methods and compositions of the invention described herein are based on the inventors' discovery and characterization of the ClpPlP2 protease complex in Mtb. As described herein, the inventors have demonstrated that ClpPlP2 is necessary for growth and virulence of Mtb. ClpPlP2 is a particularly attractive target for drug development and treatment of Mtb infections because no similar enzyme is present in the cytosol of mammalian cells. [0006] One aspect of the invention relates to a method of treating a Mycobacterium tuberculosis infection comprising administering to a subject a composition comprising an inhibitor of ClpPlP2 protease. [0007] In some embodiments, the inhibitor of ClpPlP2 protease is a small molecule. In some embodiments, the inhibitor of ClpPlP2 protease is a protein. In some embodiments, the inhibitor of ClpPlP2 protease is an intrabody. In some embodiments, the inhibitor of ClpPlP2 protease is a peptide. In some embodiments, the inhibitor of ClpPlP2 protease is a peptidomimetic. In some embodiments, the inhibitor of ClpPlP2 protease is an aptamer. In some embodiments, the inhibitor of ClpPlP2 protease is a peptide derivative. In some embodiments, the inhibitor of ClpPlP2 protease is a peptide boronate. In some embodiments, the inhibitor of ClpPlP2 protease is a beta-lactone. In some embodiments, the inhibitor of ClpPlP2 protease is a dipeptide. In some embodiments, the inhibitor of ClpPlP2 protease is a tripeptide. In some embodiments, the inhibitor of ClpPlP2 protease is a variant or fragment of ClpPl and/or ClpP2. In some embodiments, the variant or fragment of ClpPl and/or ClpP2 is a peptide or peptide mimetic. [0008] In some embodiments, the inhibitor is an inhibitor of ClpCl. In some embodiments, the inhibitor of ClpCl is selected from the group consisting of: Novo23 and hexchlorophene. [0009] Another aspect of the invention comprises a method of treating a M. tuberculosis infection comprising administering to a subject a composition comprising an activator of ClpPl P2 protease. In some embodiments, the activator is an acyldepsipeptide (ADEP). [0010] Another aspect of the invention comprises a method of treating multi-drug resistant tuberculosis (MDR-TB) or extensively drug-resistant tuberculosis (XDR-TB) comprising administering to a subject, a composition comprising an antibiotic, and a composition comprising an inhibitor or activator of ClpPlP2. In some embodiments, the antibiotic is an aminoglycoside or other anti-tuberculosis antibiotic known to those of ordinary skill in the art. [0011] In some embodiments, the antibiotic and inhibitor or activator of ClpPlP2 are co administered. In some embodiments, the antibiotic and inhibitor or activator of ClpPl P2 are sequentially administered. [0012] In one aspect, the invention comprises a method of enhancing the activity of an antibiotic comprising administering an inhibitor or activator of ClpPl P2 and the antibiotic to a subject in need of treatment for a M. tuberculosis infection. In some embodiments, the antibiotic is an aminoglycoside or other anti-tuberculosis antibiotic known to those of ordinary skill in the art. [0013] In some embodiments, the antibiotic and inhibitor or activator of ClpPlP2 are co administered. In some embodiments, the antibiotic and inhibitor or activator of ClpPl P2 are sequentially administered. [0014] In one aspect, the invention comprises a method of screening for activators of ClpPlP2 comprising, (a) contacting isolated ClpPlP2 with a detectable substrate or product thereof (e.g. an assayable substrate as described elsewhere herein, including but not limited to, Ac-PKM-amc, Ac- PWM-amc, and Ac-ARM-amc) and a candidate agent, (b) measuring the resulting level of the detectable substrate or product thereof and (c) and comparing the level of the signal from the detectable substrate with a reference signal, wherein a higher level of signal from the detectable substrate of product thereof as compared to the reference indicates the candidate agent is an activator of ClpPl P2. [0015] In one aspect, the invention comprises a method of screening for inhibitors ClpPlP2 comprising, (a) contacting isolated ClpPlP2 with a detectable substrate or product thereof (e.g. an assayable substrate as described elsewhere herein, including but not limited to, Ac-PKM-amc, Ac- PWM-amc, and Ac-ARM-amc), a candidate agent, and a control activator, (b) measuring the resulting level of signal from the detectable substrate and (c) and comparing the level of signal from the detectable substrate or product thereof with a reference signal, wherein a lower level of signal from the detectable substrate or product thereof as compared to the reference indicates the candidate agent is an inhibitor of ClpPlP2. [0016] In one aspect, the invention comprises a method of screening for a modulator of ClpPlP2 or member of the ClpPlP2 complex, the method comprising; contacting isolated ClpPlP2 with a detectable substrate, an activator, and a candidate agent; measuring the resulting level of signal from the detectable substrate; and comparing the level of signal from the detectable substrate with a reference signal, wherein a statistically significantly different level of signal from the detectable substrate as compared to the reference indicates the candidate agent is a modulator of ClpPlP2 or a member of the ClpPlP2 complex.
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