Non-Anticoagulant Low Molecular Weight Heparins for Pharmaceutical Applications

Abstract

Heparin is a polypharmacological agent with anticoagulant activity. Periodate oxidation of the nonsulfated glucuronic acid residue results in non-anticoagulant heparin derivative (NACH) of reduced molecular weight. Similar treatment of a low molecular weight heparin, dalteparin, also removes its anticoagulant activity, affording a second heparin derivative (D-NACH). A full structural characterization of these two derivatives reveals their structural differences. SPR studies display their ability to bind to several important heparin-binding proteins, suggesting potential new therapeutic applications.

Non-anticoagulant Heparin as a Pre-exposure Prophylaxis Prevents Lyme Disease Infection

“…[37][38][39] Although comparable concentrations of chondroitin sulfate and hyaluronic acids were detected in NACH-and PBS-treated mice at 24 h post-inoculation, we observed greater levels of heparan sulfate in the NACH-treated mice (Table 1). This result is in agreement with the fact that heparan sulfate has a similar disaccharide unit to NACH, 29,30 and it also verifies the bioavailability of NACH through this inoculation route. Twenty four hours after administration, the I. scapularis nymphs carrying B. burgdorferi strains B31-A3 or 297 were allowed to feed on these mice until repletion ( Figure S1).…”

“…Commercially available porcine intestinal heparin was treated with nitrous acid for depolymerization, resulting in the low molecular weight heparin, dalteparin (Figure A). This dalteparin was then oxidized with sodium periodate followed by NaBH 4 reduction as described in our previous work (Figure A). , The resulting product, NACH, was verified for its purity and low anticoagulant activity described in our recent study . We next incubated the resulting NACH products or BSA (negative control) with different low passage and infectious Lyme borreliae species or strains, including B. burgdorferi strains B31-A3 and 297 (representing two distinct genotypes associated with human infection), B. afzelii strains CB43 and VS461-JL, and B. garinii strains ZQ1 and PBr.…”

“…A low molecular weight fraction of heparin (<8000 Da) has a prolonged half-life. [27][28][29] We and others have further modified the structure of low molecular weight heparin to eliminate its anticoagulant activity. 29,30 This non-anticoagulant version of low molecular weight heparin (NACH) demonstrates no toxicity in mammalian hosts and has been used in humans for clinical trials.…”

“…These properties increase the complexity of using heparin to prevent microbial infection. A low molecular weight fraction of heparin (<8000 Da) has a prolonged half-life. − We and others have further modified the structure of low molecular weight heparin to eliminate its anticoagulant activity. , This non-anticoagulant version of low molecular weight heparin (NACH) demonstrates no toxicity in mammalian hosts and has been used in humans for clinical trials. − The improved pharmacology and safety of NACH raise the possibility of testing the ability of this compound to prevent Lyme disease infection.…”

Optimization of Heparin Monitoring with Anti-FXa Assays and the Impact of Dextran Sulfate for Measuring All Drug Activity

“…Therapy monitoring is required for drug dosage adjustment [ 10 , 11 ], especially when clearance is impaired [ 12 , 13 ], or in the presence of heparin resistance [ 14 , 15 , 16 , 17 ]. Rare and severe side effects can develop such as heparin-induced thrombocytopenia (HIT) [ 18 , 19 ]; however, heparin remains to be the anticoagulant of choice in many critical circumstances [ 1 , 8 , 20 , 21 , 22 ] and has anticoagulant activity through additional mechanisms [ 23 , 24 , 25 ]. UFH and LMWH drug dosages need to be accurately adjusted for each treated patient [ 2 , 6 , 13 , 26 , 27 ].…”