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WO 2017/092759 Al 8 June 2017 (08.06.2017) P O P C T

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WO 2017/092759 Al 8 June 2017 (08.06.2017) P O P C T (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 2017/092759 Al 8 June 2017 (08.06.2017) P O P C T (51) International Patent Classification: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 38/00 (2006.01) C07K 14/705 (2006.01) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/DK2016/050369 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, 16 November 2016 (16.1 1.2016) TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, PA 2015 70783 1 December 2015 (01 .12.2015) DK TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicant: UNIVERSITY OF COPENHAGEN DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, [DK/DK]; N0rregade 10, 1165 Copenhagen K (DK). 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, (72) Inventors: STR0MGAARD, Kristian; v llehusene 17, GW, KM, ML, MR, NE, SN, TD, TG). st.tv., 4000 Roskilde (DK). MARIC, Hans Michael; Ahle- feldtsgade 29, 2.th., 1359 Copenhagen (DK). Declarations under Rule 4.17 : (74) Agent: H0IBERG P/S; Adelgade 12, 1304 Copenhagen — of inventorship (Rule 4.17(iv)) K (DK). Published: (81) Designated States (unless otherwise indicated, for every — with international search report (Art. 21(3)) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, — with sequence listing part of description (Rule 5.2(a)) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, © o (54) Title: GEPHYRIN BINDING PEPTIDES AND USES THEREOF (57) Abstract: The present invention concerns a peptide or peptide analogue that is capable of binding gephyrin with high affinity and specificity. The invention is thus useful for modulating GlyR- or/and GABA AR mediated fast synaptic inhibition. The peptide or peptide analogue may also be used for isolation of post-synaptic density proteins and for an improved and general applicable la beling strategy to visualize inhibitory synapses. Gephyrin binding peptides and uses thereof Field of invention The present invention relates to peptides and peptide analogues which bind to gephyrin with high affinity. The invention is thus useful for therapeutic and diagnostic purposes in relation to mental or behavioural disorders and diseases of the nervous system. Background of invention Gamma-Aminobutyric acid type A receptors (GABAARs) and glycine receptors (GlyRs) are the major mediators of fast synaptic inhibition in the human brain. To fulfil this role the receptors are highly concentrated to the synaptic sites. Dysregulation of GABAAR- mediated neurotransmission has been implicated in disorders of the CNS such as epilepsy, anxiety, mood disorders, and neurodevelopmental impairments such as autism, Fragile X syndrome, and schizophrenia (Hines, Davies et al. 2012). Consequently, GABAAR agonists have been extensively explored and are widely used as clinically relevant drugs such as sedatives, anxiolytics and anticonvulsive drugs, narcotics and anaesthetics, antispasmodics, anti-epileptics, hypnotic and analgesic drugs. More recently, also GABAAR antagonists are being explored for their use in the treatment of Alzheimer's disease and cognitive deficits(Fernandez, Morishita et al. 2007, Ruby, Hwang et al. 2008), as well as neuroprotective agents(Defeudis 2002, Kiewert, Kumar et al. 2008) and pain(Zhang, L I et al. 2013). All of the aforementioned compounds act on the extracellular receptor domain and thereby also affect the physiological receptor function, potentially causing adverse side effects. The accumulation of GABAARs subtypes was shown to be dependent on gephyrin, a core component and established marker of the inhibitory post-synaptic density (Craig, Banker et al. 1996; Kim, Schrader et al. 2006; Marie, Kasaragod et al. 2014; Tyagarajan and Fritschy 2014). Thus, the direct binding of gephyrin to the intracellular regions of a subset of GABAARs and GlyRs controls the diffusion dynamics of the receptors and their synaptic clustering (Specht, Izeddin et al. 2013). In addition, gephyrin interacts only with selected subtypes of GlyRs (Kim, Schrader et al. 2006) and GABAARs (Marie, Kasaragod et al. 2014). Modulation of inhibitory transmission by targeting gephyrin has been attempted but only partial solutions have been found so far, and none that can be implemented on clinical level. One way that has been pursued is the depletion of gephyrin through genetic manipulation. Notably, both, interference with gephyrin expression by siRNA (Kirsch, Wolters et al. 1993; Yu, Jiang et al. 2007) and knockout approaches (Feng, Tintrup et al.1998; Kneussel, Brandstatter et al. 1999) as well as targeting of expressed gephyrin with intracellular antibodies (Zacchi, Dreosti et al. 2008) or dominant negative gephyrin fragments (Maas, Tagnaouti et al. 2006; Saiyed, Paarmann et al. 2007) resulted in the complete abolishment of gephyrin clusters and hence loss of GABAergic and glycinergic receptor accumulation at synaptic sites. Only very recently, an improved method was developed, which is based on gephyrin targeting intrabodies (Gross, Junge et al. 2013, Gross et al. 2016) and which allows to visualize gephyrin and hence inhibitory post-synaptic sites. The use of any chemical tool such as receptor derived gephyrin binding peptides as intra-cellular modulators of the gephyrin/receptor interaction that would not necessitate the genetic manipulations has never been reported. X-ray crystallographic studies have identified the structural requirements for gephyrin binding and it was shown that a universal binding site within gephyrin binds linear peptide motifs within distinct GlyR and GABAAR subunits, with a widely varying affinity (Kim, Schrader et al. 2006; Marie, Mukherjee et al. 201 1 ; Marie, Kasaragod et al. 2014; Brady and Jacob, 2015). Specifically, Marie et al. (2014) describe GlyR-derived peptides that bind gephyrin and are sufficient to effectively compete with other low affinity receptor fragments in vitro, however, their comparable low affinity suggests a limited use when competing with the high-affinity (Specht, Izeddin et al. 2013; Langosch, Hoch and Betz 1992) interaction of the natural full length receptors at post- synaptic sites. There is thus a need for developing compounds capable of binding with high affinity to gephyrin. mary of invention The present inventors have developed a group of peptides and peptide analogues that bind to gephyrin with exceptionally high affinity. In one aspect the present invention concerns a peptide or peptide analogue comprising at least 12 amino acid residues having a sequence X SIX2GX 3X 4PX5X6X7X8 (SEQ ID NO: 26), wherein: a . X is selected from phenylalanine (F), tyrosine (Y) b. X 2 is selected from valine (V), isoleucine (I) c . X 3 is selected from arginine (R), serine (S) d . X is selected from leucine (L), tyrosine (Y) e . X 5, X 6 and X 7 are individually selected from arginine (R) and lysine (K) f. X 8 is selected from arginine (R), lysine (K) and cysteine (C). In one aspect the invention concerns a peptide or peptide analogue comprising at least 12 proteinogenic or non-proteinogenic amino acid residues comprising or consisting of a sequence (SEQ ID NO: 33), wherein: a . X is selected from phenylalanine (F), tyrosine (Y), 3-phenylpropanoic acid, alpha-(f-butyl)hydrocinnamic acid, 4-(trifluoromethyl)hydrocinnamic acid, 3-(3,4- methylenedioxyphenyl)propionic acid, 3,3-diphenylpropionic acid, 1- naphthaleneacetic acid, 1,2,3,4-tetrahydro-2-naphthoic acid, 4-pyridinepropionic acid, L-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, D-1 ,2,3,4- tetrahydroisoquinoline-3-carboxylic acid b. X 2 and X 6 are individually selected from serine (S), arginine (R), /V-alpha- methyl-O-f-butyl-L-serine, A/,/\/'-bis-f-butyloxycarbonyl-2-amino-3-guanidino- propionic acid, A/-beta-f-butyloxycarbonyl-L-2,3-diaminopropionic acid c . X 3 and X are individually selected from valine (V), isoleucine (I), leucine (L), 3- aminopentane-3-carboxylic acid, L-cyclopentylglycine, L-cyclopropylglycine, L- cyclohexylglycine, L-Meucine, L-neopentylglycine, /V-alpha-methyl-L-isoleucine, /V-alpha-methyl-L-valine, allylglycine, L-phenylglycine, /V-alpha-methyl-L-leucine, L-cyclohexylalanine d . X 5 is selected from glycine (G), aminooxyacetic acid, sarcosine e . X 7 is selected from valine (V), isoleucine (I), leucine (L), tyrosine (Y), 3- aminopentane-3-carboxylic acid, L-cyclopentylglycine, L-cyclopropylglycine, L- cyclohexylglycine, L-Meucine, L-neopentylglycine, /V-alpha-methyl-L-isoleucine, /V-alpha-methyl-L-valine, allylglycine, L-phenylglycine, /V-alpha-methyl-L-leucine, L-cyclohexylalanine f. X 8, X g and X 0 are individually selected from arginine (R) and lysine (K) g X is selected from arginine (R), lysine (K) and cysteine (C). In one aspect the invention concerns a biologically active peptide or peptide analogue comprising at least five proteinogenic or non-proteinogenic amino acid residues comprising or consisting of the sequence X G (SEQ ID NO: 37), wherein: a . X is selected from phenylalanine (F), tyrosine (Y), 3-phenylpropanoic acid, alpha-(f-butyl)hydrocinnamic acid, 4-(trifluoromethyl)hydrocinnamic acid, 3-(3,4- methylenedioxyphenyl)propionic acid, 3,3-diphenylpropionic acid, 1- naphthaleneacetic acid, 1,2,3,4-tetrahydro-2-naphthoic acid, 4-pyridinepropionic acid, L-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, D-1 ,2,3,4- tetrahydroisoquinoline-3-carboxylic acid; b.
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