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(12) Patent Application Publication (10) Pub. No.: US 2015/0376261 A1 Steyaert Et Al US 20150376261A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0376261 A1 Steyaert et al. (43) Pub. Date: Dec. 31, 2015 (54) NOVEL CHMERIC POLYPEPTIDES FOR Publication Classification SCREENING AND DRUG DSCOVERY PURPOSES (51) Int. Cl. C07K I4/72 (2006.01) (71) Applicants: VIB VZW, Gent (BE); VRIJE C07K 6/28 (2006.01) UNIVERSITEIT BRUSSEL, Brussel GOIN33/566 (2006.01) (BE) (52) U.S. Cl. CPC ............ C07K 14/723 (2013.01); G0IN33/566 (72) Inventors: Jan Steyaert, Beersel (BE); Toon (2013.01); C07K 16/2869 (2013.01); G0IN Laeremans, Dworp (BE); Els Pardon, 2333/726 (2013.01); C07K 231 7/569 (2013.01); Lubbeek (BE) C07K 23.17/32 (2013.01); C07K 2317/75 (2013.01); C07K 2319/74 (2013.01) (21) Appl. No.: 14/764,548 (22) PCT Fled: Jan. 30, 2014 (57) ABSTRACT PCT NO.: PCT/EP2014/051845 Described are polypeptides and their use for screening and (86) drug discovery. More specifically, the disclosure provides S371 (c)(1), chimeric polypeptides comprising a membrane protein, in (2) Date: Jul. 29, 2015 particular a GPCR, fused to a binding domain, wherein the binding domain is directed against and/or specifically binds Related U.S. Application Data to the membrane protein. In particular, the chimeric polypep (60) Provisional application No. 61/758,518, filed on Jan. tides are single proteins wherein, in an intramolecular reac 30, 2013. tion, the binding domain stabilizes the membrane protein in a conformation of interest. Also provided are nucleic acid (30) Foreign Application Priority Data sequences encoding Such chimeric polypeptides, cells capable of expressing such chimeric polypeptides as well as Feb. 8, 2013 (EP) .................................. 13154552.7 cellular compositions derived thereof. Also screening meth Oct. 3, 2013 (EP) .................................. 13187265.7 ods for compounds using the chimeric polypeptides. Patent Application Publication Dec. 31, 2015 Sheet 3 of 21 US 2015/0376261 A1 FIG. 4A 100 a. IC50high- 151 E-9 M C F 50 IC50= 3,13E-6M SS O -12 10 -8 6 -4 log epinephrine), M OO C IC50high= 3.16E-9 M d F 50 IC50= 2,12E-6 M SS -12 -10 -8 -6 -4 log isoprotenerol), M Patent Application Publication Dec. 31, 2015 Sheet 4 of 21 US 2015/0376261 A1 FIG. 4C 100 e 50 IC50= 6,91E-9 M SS IC50= 1,65E-9 M logalprenolol), M FIG. 4D 100 IC50high- 990E-9 M i 50 12 ... O -8 -6 -4 log salbutamol, M Patent Application Publication Dec. 31, 2015 Sheet 5 of 21 US 2015/0376261 A1 FIG. 4E 100 c 3. SS 50 IC50= 3,59E-7M IC50= 8,27E-9 M log IC 118,551, M FIG. 4F 100 IC50= 3,96E-9 M IC50= 1,59E-9 M - 12 10 -8 -6 -4 log carvedilol), M Patent Application Publication Dec. 31, 2015 Sheet 6 of 21 US 2015/0376261 A1 FIG. 5A 100 50 IC50= 1,98E-6 M log epinephrine, M FIG. 5B 100 50 IC50= 3,96E-9 M i IC50= 8,62E-10 M 12 10 -8 -6 4. log carvedilol, M Patent Application Publication Dec. 31, 2015 Sheet 7 of 21 US 2015/0376261 A1 FIG. 6A 100 IC50high- 154E-9 M t IC50= 3,13E-6 M 50 SS 2 ... O -8 -6 r4 log epinephrine, M 100 g IC50high=m 2.75E-9 M E 50 SS IC50= 2.2OF-7 M log isoprotenerol, M Patent Application Publication Dec. 31, 2015 Sheet 8 of 21 US 2015/0376261 A1 FIG. 6C 100 c 50 IC50= 4,39E-9 M SS IC50=2,90E-9 O 12 10 -8 -6 -4 logalprenolol, M 100 g E IC50= 5,13E-6 M SS 50 log salbutamol), M Patent Application Publication Dec. 31, 2015 Sheet 9 of 21 US 2015/0376261 A1 F.G. 6E 100 IC50= 8,03E-7M F IC50= 7.75E-9 M SS log IIC 118,551), M F.G. 6F 1 OO i IC50= 2,70E-9 M log carvedilol), M Patent Application Publication Dec. 31, 2015 Sheet 10 of 21 US 2015/0376261 A1 FIG. 7 100 g F 50 SS O 2O 40 SO temperature (C) OO a. d s 50 SS - 10 -8 -6 -4 log epinephrine, M Patent Application Publication Dec. 31, 2015 Sheet 12 of 21 US 2015/0376261 A1 FIG 10A IC50high- 7, 17E-6 M R s V 2. F 50 IC50= A4,82E-4M 82E-4 SS N O -8 -6 -4 2 log carbachol, M FIG 10B s 100 IC50high- 3,11E-7 M 50 C5OH. 9,84E-5 M t log oxotremorine M, M Patent Application Publication Dec. 31, 2015 Sheet 14 of 21 US 2015/0376261 A1 F.G. 12A 100 i IC50= 3,76E-7 M log epinephrine, M FIG. 12B 100 IC50= 105E-5 M 50 IC50= 8,05E-7E.7 M ; -12 - 10 -8 6 -4 log ICI118,551), M Patent Application Publication Dec. 31, 2015 Sheet 15 of 21 US 2015/0376261 A1 FIG. 12C OO C 5 IC50= 144E-8M f 50 IC50= 1,46E-8M 12 -10 -8 -6 -4 log alprenolol, M F.G. 13A 1OO KNS N O 3. t IC50 high= 153E-9 M f IC50= 1.31 E-6 M IC50= 2,84E-M 50 SS S S O O Y E. - 2 - 11 1 0 -9 -8 . 6 5 -4 -3 2 . log epinephrine), M Patent Application Publication Dec. 31, 2015 Sheet 16 of 21 US 2015/0376261 A1 FIG. 13B 100 s IC50high= 5,41E-9 M A f IC50= 8,36E-7M IC50= 6.92E-5 M S - 12 - 11 1 0 -9 -8 -7 -6 -5 4 3 2 1 log isoprotenerol), M FIG. 13C 100 c IC50= 2,28E-8 50 t IC50= 6,04E-7 M SS IC50= 1,14E-8M 12 - 11 - 10 9 -8 -7 -6 -5 -4 3 2 - 1 log IC 118,551), M Patent Application Publication Dec. 31, 2015 Sheet 19 of 21 US 2015/0376261 A1 FIG. 16A -o- MO1-NO33 100 H. Mor1-Nb10 75 50 25 O -12 - 11 -10 -9 -8 -7 -6 -5 -4 log (Dmt1-Dalda), M FIG. 16B 100 75 O 50 25 O -12 - 11 - 10 -9 -8 -7 -6 -5 -4 log (KGOPO1), M FIG. 16C 100 75 50 25 O -12 - 11 - 10 -9 -8 -7 -6 -5 -4 log naloxone), M Patent Application Publication Dec. 31, 2015 Sheet 20 of 21 US 2015/0376261 A1 go. r . s FIG. 18A AC23506 CCS823 O O . 6 5 r -3 . w 5 -4 3. log fragment, M log fragment, M Patent Application Publication Dec. 31, 2015 Sheet 21 of 21 US 2015/0376261 A1 FIG. 18B CC43746 00 CC4494 8 8. e 5 60 25 60 #w 40 F 40 O S. S o 20 2 O . s s ra -3 f s 5 wa 3 log fragment, M. log fragment, M FIG. 18C KVO8985 AWOO89 80 80 i s 6 25 60 40 F. O S S. 2 O 7 s s 4. -3 . s 5 4. 3. log fragment, M log fragment, M 100 ... CC5623 o IC50=126E-3M a C50= 5,60E-5 M e F ... compound 9 . w 50 A C50= 2,55E-4M V. SS a C50= 3,59E-6 M W. V. W. -- compound 10 &. g IC50=248E- M N. IC50= 2,64E-6 M St. log ligand, M US 2015/0376261 A1 Dec. 31, 2015 NOVEL CHMERIC POLYPEPTIDES FOR phatases. And for many of these targets, the most stable SCREENING AND DRUG DSCOVERY conformation, corresponding to the prominent structural spe PURPOSES cies in the absence of ligands or accessory proteins (the basal conformation), does not correspond to the druggable confor CROSS-REFERENCE TO RELATED mation to which a drug must bind to be most effective for the APPLICATIONS therapeutic indication. 0001. This application is a national phase entry under 35 0005 Today, the most commonly targeted protein class for U.S.C. S371 of International Patent Application PCT/ medicinal intervention are G protein-coupled receptors EP2014/051845, filed Jan. 30, 2014, designating the United (GPCRs), also called seven-transmembrane receptors States of America and published in English as International (7TMRs). They play essential roles in physiological Patent Publication WO 2014/118297 A1 on Aug. 7, 2014, responses to a diverse set of ligands such as biogenic amines, which claims the benefit under Article 8 of the Patent Coop amino acids, peptides, proteins, prostanoids, phospholipids, eration Treaty and under 35 U.S.C. S 119(e) to U.S. Provi fatty acids, nucleosides, nucleotides, Ca" ions, odorants, sional Patent Application Ser. No. 61/758,518, filed Jan. 30, bitter and Sweet tastants, pheromones and protons (Heilker et 2013, and under Article 8 of the PCT to European Application al., 2009). Orthosteric ligands that act on a GPCR can induce Serial Nos. 13154552.7, filed Feb. 8, 2013, and 13/187265.7, a spectrum of effects on down-stream signaling pathways. In filed Oct. 3, 2013. general, GPCRs require agonist binding for activation. Full agonists maximally activate the receptor. Partial agonists STATEMENT ACCORDING TO 37 C.F.R. elicit a Submaximal stimulation even at Saturating concentra S1.821 (c) or (e) tions. In some cases, a GPCR may exhibit basal activity towards a specific signaling pathway even in the absence of an Sequence Listing Submitted as a TXT and PDF Files agonist (constitutive activity). Inverse agonists can inhibit this basal activity. Notably, whereas neutral antagonists can 0002 Pursuant to 37 C.F.R.S1.821(c) or (e), files contain inhibit binding of agonists, partial agonists, and inverse ago ing a TXT version and a PDF version of the Sequence Listing nists at the orthosteric binding site of GPCRs, they do not alter have been submitted concomitant with this application, the the basal receptor activity.
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