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WO 2018/055211 Al 29 March 2018 (29.03.2018) W !P O PCT

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WO 2018/055211 Al 29 March 2018 (29.03.2018) 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 2018/055211 Al 29 March 2018 (29.03.2018) W !P O PCT (51) International Patent Classification: Published: C12N 15/09 (2006.0 1) C12N 9/00 (2006.01) — with international search report (Art. 21(3)) A61K 45/00 (2006.01) — with sequence listing part of description (Rule 5.2(a)) (21) International Application Number: PCT/EP20 17/0744 10 (22) International Filing Date: 26 September 2017 (26.09.2017) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 16190577.3 26 September 2016 (26.09.2016) EP (71) Applicant: JOHANN WOLFGANG GOETHE- UNFVERSITAT FRANKFURT AM MAIN [DE/DE]; Theodor-W.-Adorno-Platz 1, 60323 Frankfurt am Main (DE). (72) Inventors: BHOGARAJU, Sagar; Am Hollerbusch 10, 60437 Frankfurt am Mein (DE). DIKIC, Ivan; Morfelder Landstrasse 100b, 60568 Frankfurt am Main (DE). (74) Agent: KUTTENKEULER, David; Boehmert & Boehmert, PettenkoferstraBe 20-22, 80336 Munich (DE). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, 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, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW,KZ, LA, LC, LK, LR, LS, LU, LY,MA, MD, ME, 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, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (54) Title: NOVEL COMPOUNDS AND METHODS FOR MODULATING UBIQUITINATION © (57) Abstract: The present invention pertains to the modification of the eukaryotic ubiquitin system by using the bacterial virulence factor SdeA and variants and mutants thereof. The invention is based on the phosphodiesterase activity of SdeA, which catalyzes a 00 phospho-ribosylation (or simply "ribosylation") event of ubiquitin and ubiquitin-like proteins. The invention provides SdeA proteins o and mutants without said phosphodiesterase activity, as well as medical applications of these recombinant proteins, their encoding nucleic acids, ribosylated ubiquitin proteins, and compounds which may act as selective or non-selective phosphodiesterase inhibitors. o NOVEL COMPOUNDS AND METHODS FOR MODULATING UBIQUITINATION FIELD OF THE INVENTION The present invention pertains to the modification of the eukaryotic ubiquitin system by using the bacterial virulence factor SdeA and variants and mutants thereof. The invention is based on the phosphodiesterase activity of SdeA, which catalyzes a phospho-ribosylation (or simply "ribosylation") event of ubiquitin and ubiquitin-like proteins. The invention provides SdeA proteins and SdeA mutants without said phosphodiesterase activity, as well as medical appli cations of these recombinant proteins, their encoding nucleic acids, ribosylated ubiquitin pro teins, and compounds which may act as selective or non-selective phosphodiesterase inhibi tors. DESCRIPTION The present invention pertains to a method for modulating the cellular ubiquitin system. The ubiquitin system is involved in regulating almost every cellular pathway and thus plays a crit ical role in many human diseases. Inhibiting the ubiquitin system is valuable in studying a protein's function that is prone to degradation in cells and also in treating diseases where the ubiquitin system is upregulated or misregulated. The ubiquitination cascade starts with ubiq uitin activation by a ubiquitin-activating enzyme (El), which forms a high energy thioester linkage with the C-terminus of ubiquitin in the presence of ATP as the energy source. E l in teracts with a ubiquitin-conjugating enzyme (E2) and ubiquitin is transferred to the E2 via a trans-thioesterification reaction. Finally, with the help of a ubiquitin ligase (E3), ubiquitin is typically attached to a lysine residue on a protein substrate, forming an isopeptide bond via its C-terminus. Depending on the type of modification (mono-, poly-, or multi-ubiquitination), the modified substrate protein can be targeted for proteasomal degradation, or can change its cellular localization, interaction partners or enzymatic function. The main cellular machinery for the degradation of intracellular proteins is the ubiquitin- proteasome system. Substrates tagged with a poly-ubiquitin tail are marked for degradation by the proteasome. In eukaryotes, proteins are constantly synthesized and degraded, the configu ration of the proteasome is responsible for the degradation of proteins into short peptide frag- ments. Because of the enormous destructive potential of the proteasome, both its localization and activity in a cell is under tight control. Only proteins that are marked with a covalently linked poly-ubiquitin tail of at least 4 mono-ubiquitin molecules in length can enter the pro teasome and are subsequently degraded into short peptide fragments. Not all proteins require poly-ubiquitination before proteasomal degradation. One notable exception is ornithine d e carboxylase (ODC) which activates its degradation by the proteasome via a direct interaction with a regulatory subunit. Because of the involvement of the proteasome in many important cellular processes it has become a target of interest in the search of novel therapies for a wide variety of diseases. For instance, proteasome inhibitors have already proven themselves to be of great therapeutic val ue as illustrated by the approval of Velcade® (bortezomib) for the treatment of multiple mye loma and mantle cell lymphoma. In contrast to proteasome inhibition, proteasome activation is a relatively new field. Increasing the proteolytic capacity of cells could have potential ther apeutic applications for the treatment of e.g. neurodegenerative diseases. The identification of proteasome modulators and the study of their regulating dynamics will contribute to the gen eral knowledge about proteasome activity and assist in the development of new therapies for a variety of diseases. Given the essential roles of ubiquitination in the regulation of the immune system, it is not surprising that the ubiquitination network is a common target for diverse infectious agents. For example, many bacterial pathogens exploit ubiquitin signaling using virulence factors that function as E3 ligases, deubiquitinases or as enzymes that directly attack ubiquitin. The bacte rial pathogen Legionella pneumophila utilizes approximately 300 effectors that modulate d i verse host processes to create a permissive niche for its replication in phagocytes. Recently it was demonstrated that a member of the SidE effector family of L. pneumophila, the protein SdeA, ubiquitinates multiple Rab small GTPases associated with the endoplasmic reticulum without the need for the E l and E2 enzymes (Qui J et al, "Ubiquitination inde pendent of E l and E2 enzymes by bacterial effectors."; Nature. 2016 May 5;533(7601):120-4. doi: 10.1038/naturel7657. Epub 2016 Apr 6.). This El/E2-independent ubiquitination cata lyzed by SdeA is energized by nicotinamide adenine dinucleotide, which activates ubiquitin by the formation of ADP-ribosylated ubiquitin. These results establish that ubiquitination can be catalyzed by a single enzyme, the activity of which does not require ATP. In view of the state of the art it was an object of the invention to provide novel approaches for the modulation, in particular the impairment, of the ubiquitin-proteasome system in eukary- otes. Furthermore the invention seeks to provide compounds usable in methods for the modu lation of the ubiquitin system and the application of these compounds in the treatment of the various ubiquitin- and proteasome-associated disorders. The above problem is solved in a first aspect by a method of deactivating, blocking and/or impairing the ubiquitin system in a cell, comprising introducing into the cell a recombinant SdeA protein, or a recombinant SdeA protein derivative, wherein the SdeA protein, or the recombinant SdeA protein derivative, comprises at least an ADP-ribosyl transferase domain. In context of the present invention a "SdeA protein" is preferably a protein having the amino acid sequence as shown in SEQ ID NO: 1. SdeA in context of the invention shall be under stood to be a protein comprising at least the enzymatic domains: deubiquitinating protease (DUB), phosphodiesterase domain and a ADP-ribosyltransferase domain. In one alternative embodiment the SdeA protein of the invention is a protein, comprising an amino acid se quence having at least 80%, preferably 85%, 90%, 95%, 96%, 97%, most preferably 98% or 99% sequence identity to the sequence shown in SEQ ID NO: 1. In some embodiments of the invention a recombinant SdeA protein derivative is a fragment of the full length SdeA protein as shown in SEQ ID NO:l. Such a fragment is preferably a m in imal but functional SdeA protein, preferably comprising amino acids 150 to 950 (+/- 50, pref erable 20, 10 or 5 amino acids on either end) of the SEQ ID NO: 1, more preferably amino acids 213 to 907 of SEQ ID NO: 50, preferable 20, 10 or 5 amino acids on either end). In some embodiments it is preferable that the SdeA protein used in the methods of the inven tion is a recombinant SdeA protein, or a recombinant SdeA protein derivative, which does not comprise a functional phosphodiesterase domain.
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