TY - JOUR
T1 - End-Site-Specific Conjugation of Enoxaparin and Tetradeoxycholic Acid Using Nonenzymatic Glycosylation for Oral Delivery
AU - Park, Jooho
AU - Jeon, Ok Cheol
AU - Yun, Jisuk
AU - Nam, Hwajung
AU - Hwang, Jinha
AU - Al-Hilal, Taslim A.
AU - Kim, Kwangmeyung
AU - Kim, Kyungjin
AU - Byun, Youngro
N1 - Funding Information:
This work was supported by Korea Drug Development Fund (Grant KDDF-201408-03). This study was also supported by Basic Science Research Program (Grant 2010-0027955) of the National Research Foundation of Korea (NRF) and Cancer Control (Grant 1420390), Ministry of Health and Welfare.
Publisher Copyright:
© 2016 American Chemical Society.
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2016/12/8
Y1 - 2016/12/8
N2 - Heparin and low molecular weight heparins (LMWHs) have been the drug of choice for the treatment or the prevention of thromboembolic disease. Different methods are employed to prepare the LMWHs that are clinically approved for the market currently. In particular, enoxaparin, which has a reducing sugar moiety at the end-site of polysaccharide, is prepared by alkaline depolymerization. Focusing on this end-site-specific activity of LMWHs, we conjugated the tetraoligomer of deoxycholic acid (TetraDOCA; TD) at the end-site of enoxaparin via nonenzymatic glycosylation reaction. The end-site-specific conjugation is important for polysaccharide drug development because of the heterogeneity of polysaccharides. This study also showed that orally active enoxaparin and tetraDOCA conjugate (EnoxaTD) had therapeutic effect on deep vein thrombosis (DVT) without bleeding in animal models. Considering the importance of end-specific conjugation, these results suggest that EnoxaTD could be a drug candidate for oral heparin development.
AB - Heparin and low molecular weight heparins (LMWHs) have been the drug of choice for the treatment or the prevention of thromboembolic disease. Different methods are employed to prepare the LMWHs that are clinically approved for the market currently. In particular, enoxaparin, which has a reducing sugar moiety at the end-site of polysaccharide, is prepared by alkaline depolymerization. Focusing on this end-site-specific activity of LMWHs, we conjugated the tetraoligomer of deoxycholic acid (TetraDOCA; TD) at the end-site of enoxaparin via nonenzymatic glycosylation reaction. The end-site-specific conjugation is important for polysaccharide drug development because of the heterogeneity of polysaccharides. This study also showed that orally active enoxaparin and tetraDOCA conjugate (EnoxaTD) had therapeutic effect on deep vein thrombosis (DVT) without bleeding in animal models. Considering the importance of end-specific conjugation, these results suggest that EnoxaTD could be a drug candidate for oral heparin development.
UR - http://www.scopus.com/inward/record.url?scp=85003632913&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85003632913&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.6b00936
DO - 10.1021/acs.jmedchem.6b00936
M3 - Article
C2 - 27933952
AN - SCOPUS:85003632913
VL - 59
SP - 10520
EP - 10529
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 23
ER -