news of the week MARCH 3, 2014 EDITED BY WILLIAM G. SCHULZ & SOPHIA L. CAI
NEW ROUTE TO IMPROVED HEPARINS DRUG DISCOVERY: Chemoenzymatic
analogs may sidestep key problems of current anticoagulants
R
HO HO
ESEARCHERS HAVE USED chemoenzymatic
synthesis to create new forms of heparin that may solve key problems with current versions of the medication. Heparin, a sugar-based polymer, is widely used to reduce blood clotting in patients who have thrombosis and other conditions. Two of the three commercial forms of OSO3– heparin—unfractionated O heparin and low-molecuOSO3– – O
NH O
HO
CO2
O
O – HO O3SO
O –O
3SHN
–O
2C
O
OSO3–
OH O
O HO
O –O
–O
2C
SHN O
3
therefore addresses the inhomogeneity problems of porcine heparins. It may be possible to administer it to kidney-impaired patients because it appears to be cleared, at least in part, through the liver. Its effects can be reversed by coadministering an approved drug called protamine. And it’s easier to synthesize than fondaparinux, requiring 22 steps. Although heparin is most frequently used as an anticoagulant, it may also have anticancer, anti-inflammatory, and antiviral activities. The chemoenzymatic synthesis can be fine-tuned to enhance different heparin activities, Linhardt says. It might also make it possible to synthesize heparins that are easier to administer, last longer, and are optimally cleared from the body. Jeffrey I. Weitz, a specialist in hematology and thromboembolism at McMaster University, in Ontario, comments that the new agent’s “potential for complete protamine reversal may render chemosynthetic low-molecular-weight heparins better choices than enoxaparin,” a widely prescribed porcine heparin, “for treatment of paOSO – 3
OH
O
O HO
–O C OSO3– lar-weight heparin—are 2 OH –O SHN derived from pig intestines. O O 3 – – O O OSO3– O3SO O2C That means they are inhomogeneous mixtures of OH –O SO – O SHN O 3 O 3 –O SO O sulfated carbohydrates of different sizes and variable O 3 CO2– HO – sulfation patterns, leaving them open to batch-to-batch O O3SHN O –O SO 3 O variations and uncertain efficacies. Their animal source HO HO also makes them subject to virus and prion impurities Chemoenzymatic dodecasaccharide (top) shows and other types of contamination, some of which have better drug properties and is easier to synthesize than fondaparinux (bottom), a pentasaccharide. caused patient deaths. The third form, a synthetic pentasaccharide called fondaparinux, is a pure substance. But its effects are tients at high risk OSO3– irreversible: It lacks an antidote when anticoagulant for bleeding, O HO OSO3– activity becomes excessive. Fondaparinux is primarily such as those CO2– HO – O O SHN excreted through the kidneys, giving it long persistence who have unO O 3 O – OSO3– O2C HO – in patients with kidney disease, for whom it is therefore dergone recent OH HO O3SO – O3SHN O O O unsuitable. Furthermore, it is difficult to synthesize, surgery.” O HO – requiring 50 steps. If its liver excretion properties O3SHN OCH3 –O SO 3 Robert J. Linhardt of Rensselaer Polytechnic Inare confirmed, the new heparin could also be stitute; Jian Liu of the University of North Carolina, useful in patients with severe renal impairment, for Chapel Hill; and coworkers have now used chemoenzy- whom enoxaparin and fondaparinux cannot be used, matic synthesis to develop new heparin variants (Nat. Weitz adds. “This would be an important advance,” he Chem. Biol. 2014, DOI: 10.1038/nchembio.1459). notes. But he cautions that its ease of administration, Up to now, the ability to develop improved heparin anticoagulant activity over time, mode of excretion, therapeutics “has largely been hindered by an inability and potential to lower the amount of blood platelets, to synthesize these complex molecules,” Liu says. “Our a serious complication of heparin therapy, still need new chemoenzymatic method opens the possibility to to be evaluated. expand heparin-based medicines for a wide variety of Liu says the team plans to determine whether clinical indications.” large-scale synthesis of the chemosynthetic agents The most promising new heparin variant they is feasible and hopes “to license the technology to synthesized is a dodecasaccharide (12-unit sugar). It a business partner for drug development.”—STU is a pure synthetic substance like fondaparinux and BORMAN –O SO 3
O
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MARCH 3, 2014
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