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(12) Patent Application Publication (10) Pub. No.: US 2009/0068738A1 BERTOZZ Et Al US 20090068738A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0068738A1 BERTOZZ et al. (43) Pub. Date: Mar. 12, 2009 (54) COMPOSITIONS AND METHODS FOR Related U.S. Application Data MODIFICATION OF BOMOLECULES (63) Continuation-in-part of application No. 1 1/264,463, filed on Oct. 31, 2005. (75) Inventors: CAROLYN RUTH BERTOZZI, (60) Provisional application No. 60/624.202, filed on Nov. BERKELEY, CA (US); 1, 2004. NICHOLAS J. AGARD, BERKELEY, CA (US); Publication Classification JENNIFER A. PRESCHER, (51) Int. Cl. BERKELEY, CA (US): JEREMY CI2N 5/06 (2006.01) MICHAEL BASKIN, C07D 495/04 (2006.01) BERKELEY, CA (US); ELLEN CD7C 65/26 (2006.01) MAYSLETTEN, BERKELEY, CA C7H I/00 (2006.01) (US) (52) U.S. Cl. ...................... 435/375: 548/304.1; 540/480; 562/473; 536/55.3 Correspondence Address: (57) ABSTRACT BOZICEVIC, FIELD & FRANCIS LLP The present invention provides modified cycloalkyne com 1900 UNIVERSITY AVENUE, SUITE 200 pounds; and method of use of Such compounds in modifying EAST PALOALTO, CA 94.303 (US) biomolecules. The present invention features a cycloaddition reaction that can be carried out under physiological condi (73) Assignee: THE REGENTS OF THE tions. In general, the invention involves reacting a modified UNIVERSITY OF cycloalkyne with an azide moiety on a target biomolecule, CALIFORNLA, Oakland, CA (US) generating a covalently modified biomolecule. The selectiv ity of the reaction and its compatibility with aqueous envi ronments provide for its application in Vivo (e.g., on the cell (21) Appl. No.: 12/049,034 Surface or intracellularly) and in vitro (e.g., synthesis of pep tides and other polymers, production of modified (e.g., (22) Filed: Mar. 14, 2008 labeled) amino acids). R / Cu(l), ligand N f R-N -- E R' N R Patent Application Publication Mar. 12, 2009 Sheet 1 of 13 US 2009/0068738A1 Figures 1A and 1B A R N Cu(l), ligand N. f R-N + E R' N B > R" strain-promoted N / f 2. R" R-N + - C- N Patent Application Publication Mar. 12, 2009 Sheet 2 of 13 US 2009/0068738A1 Figure 2 AZ: O-biotin Patent Application Publication Mar. 12, 2009 Sheet 3 of 13 US 2009/0068738A1 Figures 3A-C 5OO 800 es - 400 s9 600 S 300 ( 400 (O + AZ 4) T. (> 200 1 OO ( O -- --w t O t s O 200 400 600 800 1 000 O 30 60 90 12O C 5 (uM) Time (min) 120 D - sc 80 is 40 O wo No reagent 5 phosphine Patent Application Publication Mar. 12, 2009 Sheet 4 of 13 US 2009/0068738A1 Figure 4A (a) O ACO HN-N: ACO O N 1. 1-FLAG Or AcMannAz FITC OFLAG Figure 4B (b) 70 60 SO 40 30 20 O no reagent i-FLAG (250 M) 12b-FLAG (250M) 12b-FLAG (1000 MD 12b-FLAG (2500 MD Patent Application Publication Mar. 12, 2009 Sheet 5 of 13 US 2009/0068738A1 Figure 5 splenocyte labeling (PBS) FLAG conjugates 12O gri------------ OO 80 i -Az i +25 uMAC4Man NAZ 40 no reagent Phos-FLAG (100 oct-FLAG (100 F-oct-FLAG (100 ALO-FLAG (100 uM) uM) uM) uM) Patent Application Publication Mar. 12, 2009 Sheet 6 of 13 US 2009/0068738A1 Figure 6 150 120 90 ex ViVO 60 labeling 30 MannAz H H H PhOS/AO-F AG H H H H Patent Application Publication Mar. 12, 2009 Sheet 7 of 13 US 2009/0068738A1 Figure 7 No Reagent Azacyclooctyne 200 kDa 00 60 40 30 Patent Application Publication Mar. 12, 2009 Sheet 8 of 13 US 2009/0068738A1 Figure 8 Jurkat Cell Surface Labieing 160 140 120 OO 40 Patent Application Publication Mar. 12, 2009 Sheet 9 of 13 US 2009/0068738A1 Figure 9 0 0 0. Aciania Patent Application Publication Mar. 12, 2009 Sheet 10 of 13 US 2009/0068738A1 Figure 10 time irrin 8 is 3: ; c. Cr-fre: tick ch:88istry (EFO C-catalyxei Kick citeristry Patent Application Publication Mar. 12, 2009 Sheet 11 of 13 US 2009/0068738A1 Figures 11A and 11B A. 3 83 reaget Steadinger s ligatics: Strait-praysotsd. cycicadditics Ci-free click t:Eternistry {F}} 88. 338 23: . : OF)-biotii it Patent Application Publication Mar. 12, 2009 Sheet 12 of 13 US 2009/0068738A1 Figure 12 Comparative cell-surface azide labeling efficiency of DIFO, DIFO2, and DIFO3 1400 1200 1OOO 800 6OO 400 2OO ... norgt DIFO DIFO2 DIFO3 biotin conjugate (10 uM, 1 h rxn) Patent Application Publication Mar. 12, 2009 Sheet 13 of 13 US 2009/0068738A1 Figure 13 Concentration dependence of DIFO2-biotin and DIFO3 biotin cell-surface azide labeling 6OO 0 DIFO2 - AC4Man NAZ E DIFO3 - AC4Man NAZ 500 A DIFO2 -AC4Man NAZ 4OO O DIFO3 -AC4Man NAZ 3OO 2OO 1OO O O 2 4. 6 8 1O 12 DIFO2-biotin or DIFO3-biotin US 2009/0068738A1 Mar. 12, 2009 COMPOSITIONS AND METHODS FOR 0006. There is a need in the field for additional mecha MODIFICATION OF BOMOLECULES nisms to modify biological molecules through a biocompat ible reaction, particularly in a biological environment. CROSS-REFERENCE Literature 0001. This application is a continuation-in-part of U.S. 0007 Huisgen (1963) Angew. Chem. Int. Ed. 2:565-598; patent application Ser. No. 1 1/264,463, filed Oct. 31, 2005, Shea and Kim. J. Am. Chem. Soc. 1992, 114, 4846-4855; which claims the benefit of U.S. Provisional Patent Applica Reese and Shaw (1970) Chem. Comm. 1172-1173; Wilbur et tion No. 60/624.202 filed Nov. 1, 2004, which applications al. Bioconi. Chem. 1996, 7, 689-702: Bistrup et al. J. Cell are incorporated herein by reference in their entirety. Biol. 1999, 145, 899-910; Saxon et al. J. Am. Chem. Soc. 2002, 124, 14893-14902; Hang and Bertozzi. Acc. Chem. Res. 2001, 34, 727-736: Link et al. Curr. Opin. Biotechnol. STATEMENT REGARDING FEDERALLY 2003, 14, 603-609; Lee et al. J. Am. Chem. Soc. 2003, 125, SPONSORED RESEARCH 9588-9589; Wang et al. J. Am. Chem. Soc, 2003, 125, 3192 3193: Kiick et al. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 0002 The U.S. government may have certain rights in this 19-24: Speers and Cravatt. Chem. Biol. 2004, 11, 535-546; invention, pursuant to grant nos. ROI GM58867 awarded by Saxon and Bertozzi Science 2000, 287, 2007-2010; Link, A. the National Institutes of Health. J.; Tirrell, D. A. J. Am. Chem. Soc. 2003, 125, 1164-1165; Dube and Bertozzi. Curr. Opin. Chem. Biol. 2003, 7, 616 FIELD OF THE INVENTION 625; Vocadlo et al. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 9116-9121; Prescher et al. Nature 2004, 430, 873-877; Seo et 0003. The invention relates generally to covalent modifi al. J. Org. Chem. 2003, 68, 609-612: Li et al. Tetrahedron cation of molecules useful in, for example, modification of Lett. 2004, 45, 3143-3146; Wittig and Krebs. Chem. Ber: Surfaces (including cell Surfaces), and modification of mol 1961, 94, 3260-3275; Meier et al. Chem. Ber: 1980, 113, ecules under physiological conditions (e.g., in a cellular envi 2398-2409: Turner et al. J. Am. Chem. Soc. 1972, 95, 790 ronment). 792. SUMMARY OF THE INVENTION BACKGROUND OF THE INVENTION 0008. The present invention provides modified 0004 Selective chemical reactions that are orthogonal to cycloalkyne compounds; and method of use of Such com the diverse functionality of biological systems are now rec pounds in modifying biomolecules. The present invention ognized as important tools in chemical biology. As relative features a cycloaddition reaction that can be carried out under newcomers to the repertoire of synthetic chemistry, these physiological conditions. In general, the method involves bioorthogonal reactions have inspired new strategies for com reacting a modified cycloalkyne with an azide moiety on a pound library synthesis, protein engineering, functional pro target biomolecule, generating a covalently modified biomol teomics, and chemical remodeling of cell Surfaces. The azide ecule. The selectivity of the reaction and its compatibility has secured a prominent role as a unique chemical handle for with aqueous environments provide for its application in vivo bioconjugation. The Staudinger ligation has been used with (e.g., on the cell Surface or intracellularly) and in vitro (e.g., phosphines to tag azido Sugars metabolically introduced into synthesis of peptides and other polymers, production of cellular glycoconjugates. The Staudinger ligation can be per modified (e.g., labeled) amino acids). formed in living animals without physiological harm; never theless, the Staudinger reaction is not without liabilities. The BRIEF DESCRIPTION OF THE DRAWINGS requisite phosphines are susceptible to air oxidation and their optimization for improved water solubility and increased 0009 FIGS. 1A and 1B depict cycloaddition reactions. reaction rate has proven to be synthetically challenging. FIG. 1A depicts Cu(I)-catalyzed Huisgen cycloaddition 0005. The azide group has an alternative mode of bioor ("click chemistry'). FIG. 1B depicts strain-promoted 3+2 thogonal reactivity: the 3+2] cycloaddition with alkynes cycloaddition of azides and cyclooctynes. described by Huisgen. In its classic form, this reaction has (0010 FIG.2 depicts labeling of azide-modified GlyCAM limited applicability in biological systems due to the require Ig with alkyne probes. ment of elevated temperatures (or pressures) for reasonable (0011 FIGS. 3A-C depict cell surface labeling with a reaction rates. Sharpless and coworkers surmounted this modified cyclooctyne compound. obstacle with the development of a copper(I)-catalyzed ver sion, termed "click chemistry, that proceeds readily at physi 0012 FIG. 4A schematically depicts labeling of cell-sur ological temperatures and in richly functionalized biological face azides with cyclooctyne probes. environs. This discovery has enabled the selective modifica 0013 FIG.
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