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(12) Patent Application Publication (10) Pub. No.: US 2009/0035787 A1 Liu Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2009/0035787 A1 Liu Et Al US 20090035787A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0035787 A1 Liu et al. (43) Pub. Date: Feb. 5, 2009 (54) ENZYMATIC SYNTHESIS OF SULFATED Publication Classification POLYSACCHARDES WITHOUT DURONIC ACID RESIDUES (51) Int. Cl. GOIN 33/53 (2006.01) (75) Inventors: Jian Liu, Chapel Hill, NC (US); COSB 37/10 (2006.01) Courtney Jones, Durham, NC CI2P 19/26 (2006.01) (US); Jinghua Chen, Wuhan (CN); CI2O 1/02 (2006.01) Yongmei Xu, Chapel Hill, NC (US) C40B 50/06 (2006.01) Correspondence Address: (52) U.S. Cl. .............. 435/7.1:536/21:536/122; 435/84; JENKINS, WILSON, TAYLOR & HUNT, P. A. 506/26: 435/15; 435/29 Suite 1200 UNIVERSITY TOWER, 3100 TOWER BLVD., (57) ABSTRACT DURHAM, NC 27707 (US) Iduronic acid (Idol JA)-free heparan sulfate (HS)-like com (73) Assignee: The University of North Carolina pounds are provided. Also provided are methods of synthe at Chapel Hill sizing Idol JA-free HS-like compounds. The methods can include providing at least one O-sulfotransferase (OST) (21) Appl. No.: 12/178,434 enzyme and a reaction mixture comprising 3'-phosphoad enosine 5'-phosphosulfate (PAPS); and incubating a polysac (22) Filed: Jul. 23, 2008 charide substrate with the at least one OST and the reaction mixture, whereby the HS-like compounds are synthesized. Related U.S. Application Data Also disclosed are methods of synthesizing a library of HS (60) Provisional application No. 60/961,716, filed on Jul. like compounds and methods of determining the mechanism 23, 2007. of activity of HS-like compounds. 6 HOHC O HCHC HOHC O O Hoog "\,'\ H00 \O \ E \\?ion).0 (09 HO A. YO O ty NDST O HO pi HO OH NHSOH Ho M"HO Ngcl. HO OH (IDURONICACID, Idol)A) (GLCURONICACID, GlcA) (ACETYLCLUCOSAMINE,O GlcNAc) (N-SULFOGLUCOSAMINE, GLcNS) po H03SOHC 0 H03SCHy( 0 (Osc) HOHy( 0 H00C O \ O \ O Ho Y \O O to 1 \, , 6-0ST NHSOH HO-My NHSOHA3' oso NHSOH3 3-0ST HO-1 bso NHSOH3 (6-0, 3-0, YSULFO (6-O-SULFOGLUCOSAMINE, (2-0SULFOIDURONICACID, IdoA2S) GLUCOSAMINE, GlcNS3S6S) NDS. N-DEACEYLASE/N-SULFOTRANSFERASE 3-0ST. 3-O-SUFOTRANSFERASE 6-0ST. -O-SUFOTRANSFERASE 2-0ST 2-O-SUFORANSFERASE Epi- EPIMERASE US 2009/0035787 A1 HSVHWICH-Id] Patent Application Publication Feb. 5, 2009 Sheet 2 of 8 US 2009/0035787 A1 Patent Application Publication Feb. 5, 2009 Sheet 3 of 8 US 2009/0035787 A1 Figure 2. A. e--5 - compound 8 4. SO 80 1OO - Compound 2 40 6O BO 1OO Retention Time (min) Patent Application Publication Feb. 5, 2009 Sheet 4 of 8 US 2009/0035787 A1 Figure 3. 2O Heparir . Compound 8 Compound 2 Compound 1 Compound 7 SO A. O 0.0 O5 1.O 15 2.O. Concentration of polysaccharide (g/ml) Patent Application Publication Feb. 5, 2009 Sheet 5 of 8 US 2009/0035787 A1 Figure 4. 8000 0.35 -- *s (cpm) O.30 -- O.D. 232 6OOO m 0.25 area 0.20 E E CN SlC 0.15 ()N VO ? g 0.10 C O.05 O.OO 2O 30 40 50 60 70 Fraction Number Patent Application Publication Feb. 5, 2009 Sheet 6 of 8 US 2009/0035787 A1 Figure 5. s 1OO without epimerase and 2-0ST t E: With epimerase and 2-0ST D 3. 80 s 3 3 60 o 40 is2 20 e s O D- Tetra. Hexa- Octa- Deca- -Dodeca- Full length Size of Substrates Patent Application Publication Feb. 5, 2009 Sheet 7 of 8 US 2009/0035787 A1 Figure 6. HOHC HOHC HOOC OOC O N-sulfotransferase Yo o / Yo o 1 HO NHSOH O Deacetylated Heparosan PAPS EAF N-sulfo Heparosan (8 mg) (6 mg) : HQ HOS PAPS O and6-OST-1 6-OST-3 PAPS D PAF (PNP)NO2 HOSOHC HOSOHC O HOOC 3 O O HOOC HOSC O O. o1 os- no OHO b1 Yo NHSOH 7 S. HO NHSOH HO OH PA PAS OH N-sulfo Heparosan 6-O-sulfated Recomparin (2 mg) PAPS Regeneration (4 mg) Patent Application Publication Feb. 5, 2009 Sheet 8 of 8 US 2009/0035787 A1 O OO Hepari (rg/ml) B 100 2. 1. 100 Recomparin (g/ml) US 2009/0035787 A1 Feb. 5, 2009 ENZYMATC SYNTHESIS OF SULFATED POLYSACCHARDES WITHOUT DURONIC ACID RESIDUES L2 COOH L CHOR3 L2 RELATED APPLICATIONS 1N O 1N O 1N H H 0001. This application claims the benefit of U.S. Provi Y KOR. H. Y KOR, H, Y sional Patent Application Ser. No. 60/961,716, filed Jul. 23, H H H H 2007; the disclosure of which is incorporated herein by ref erence in its entirety. H OR GOVERNMENT INTEREST whereinX is NH or O, R is H, SOH or CH, R is SOH, R 0002 The presently disclosed subject matter was made is Hor SOH, R is H, SOH, CH, or CHCHR is H, SOH, with U.S. Government support under Grant No. AI50050 CH or CHCH R is COOH, COOCH, COOCHs. awarded by National Institutes of Health. Thus, the U.S. CHOSOH, or CHSOH, L is an alpha or beta linkage, L. Government has certain rights in the presently disclosed Sub is an alpha or beta linkage, Y is O or N, and n is 24. In some ject matter. embodiments, the Idol JA-free HS-like compound is provided wherein X is NH, R is SOH, R is SOH, R is SOH, R is TECHNICAL FIELD Hor SOH. Rs is H. L. is an alpha or a beta linkage, L is an 0003. The presently disclosed subject matter relates gen alpha or a beta linkage, and n is 24. In some embodiments, erally to methods of Sulfating polysaccharides. In some the Idol JA-free HS-like compound is provided wherein L is embodiments, the presently disclosed subject matter relates an alpha linkage and L is a beta linkage. to methods of Sulfating polysaccharides using O-sulfotrans 0007. In some embodiments, the Idol JA-free HS-like ferases. compound has a binding affinity to antithrombin ranging from about 20 to about 60 nM. In some embodiments, the BACKGROUND Idol JA-free HS-like compound has an anti-Xa activity rang ing from about 10 to about 500 ng/ml. In some embodiments, 0004 Heparan sulfate (HS) is a ubiquitous component of the Idol JA-free HS-like compound has an anti-IIa activity the cell surface and extracellular matrix. It regulates a wide ranging from about 5 to about 200 ng/ml. In some embodi range of physiologic and pathophysiologic functions, includ ments, the Idol JA-free HS-like compound has substantially ing embryonic development and blood coagulation, and can reduced cell proliferation activity as compared to a HS-like facilitate viral infection (Esko and Selleck (2002) Annu. Rev. compound with iduronic acid residues. Biochem. 71, 435-471; Liu and Thorp (2002) Med. Res. Rev. 0008. In some embodiments, the Idol JA-free HS-like 22, 1-25). HS exerts its biological effects by interacting with compound is provided wherein R is selected from the group the specific proteins involved in a given process (Capila and consisting of CH, CHCH and SOH and Rs is selected Lindhardt (2002) Angew. Chem. Int Ed 41,390-412). HS is a from the group consisting of CH, CHCH and SOH. In highly charged polysaccharide comprising 1->4-linked glu some embodiments, the Idol JA-free HS-like compound is cosamine and glucuronic/iduronic acid units that contain both provided wherein X is O and R is SOH. In some embodi N- and O-sulfo groups. Unique Saccharide sequences within ments, the Idol JA-free HS-like compound is provided HS determine the specificity of the binding of HS to its target wherein L is an alpha linkage and L is an alpha linkage. In proteins (Linhardt (2003) J. Med. Chem. 46, 2551-2564). some embodiments, the Idol JA-free HS-like compound is Heparin, a specialized form of HS, is a commonly used anti provided wherein L is a beta linkage and L is a beta linkage. coagulant drug. Thus, new methods for the synthesis of hep 0009. In some embodiments of the presently disclosed arin and HS attract considerable interest for those developing subject matter, a method of synthesizing an Idol JA-free HS anticoagulant and other HS-related drugs having improved like compound is provided, comprising incubating a polysac pharmacological effects. charide Substrate with a Sulfo donor compound and an enzyme mixture, the enzyme mixture comprising O-sul SUMMARY fotransferase (OST) enzymes 6-OST-1,6-OST-3 and 0005. This Summary lists several embodiments of the 3-OST-1 and substantially no epimerase enzyme, wherein presently disclosed subject matter, and in many cases lists synthesis of the Idol JA-free HS-like compound from the variations and permutations of these embodiments. This polysaccharide Substrate is accomplished. In some embodi Summary is merely exemplary of the numerous and varied ments, the method comprises a polysaccharide Substrate embodiments. Mention of one or more representative features selected from the group consisting of N-sulfo heparosan and of a given embodiment is likewise exemplary. Such an chemically desulfated N-sulfated heparin. In some embodi embodiment can typically exist with or without the feature(s) ments, the OST enzymes are recombinant OST enzymes. In mentioned; likewise, those features can be applied to other some embodiments, the recombinant OST enzymes are pro embodiments of the presently disclosed subject matter, duced in a bacterial expression system. In some embodi whether listed in this Summary or not. To avoid excessive ments, the Sulfo donor compound comprises a compound repetition, this Summary does not list or Suggest all possible capable of donating a Sulfonate or Sulfuryl group.
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