As detailed in the table below, there is a great deal of potential for the development of heparin-like structures as drugs to treat a wide range of diseases, in addition to their current use as anticoagulants.
| Disease states sensitive to heparin | Heparins effect in experimental models | Clinical status |
|
| Adult respiratory distress syndrome | Reduces cell activation and accumulation in airways, neutralizes mediators and cytotoxic cell products, and improves lung function in animal models | Controlled clinical trials |
|
| Allergic encephalomyelitis | Effective in animal models | - |
|
| Allergic rhinitis | Effects as for adult respiratory distress syndrome, although no specific nasal model has been tested | Controlled clinical trial |
|
| Arthritis | Inhibits cell accumulation, collagen destruction and angiogenesis | Anecdotal report |
|
| Asthma | As for adult respiratory distress syndrome, however it has also been shown to improve lung function in experimental models | Controlled clinical trials |
|
| Cancer | Inhibits tumour growth, metastasis and angiogenesis, and increases survival time in animal models | Several anecdotal reports |
|
| Delayed type hypersensitivity reactions | Effective in animal models | - |
|
| Inflammatory bowel disease | Inhibits inflammatory cell transport in general. No specific model tested | Controlled clinical trials |
|
| Interstitial cystitis | Effective in a human experimental model of interstitial cystitis | Related molecule now used clinically |
|
| Transplant rejection | Prolongs allograft survival in animal models | - |
- indicates no information available
As a result of heparin's effect on such a wide variety of disease states a number of drugs are indeed in development whose molecular structures are identical or similar to those found within parts of the polymeric heparin chain. This bacterium is capable of utilizing either heparin or HS as its sole carbon and nitrogen source. In order to do this it produces a range of enzymes such as lyases, glucuronidases, sulfoesterases and sulfamidases. It is the lyases that have mainly been used in heparin/HS studies. The bacterium produces three lyases, heparinases I, II and III and each has distinct substrate specificities as detailed below.
| Heparinase enzyme | Substrate specificity |
|
| Heparinase I | GlcNS(±6S)-IdoA(2S) |
| Heparinase II | GlcNS/Ac(±6S)-IdoA(±2S)
GlcNS/Ac(±6S)-GlcA |
| Heparinase III | GlcNS/Ac(±6S)-GlcA/IdoA (with a preference for GlcA) |
The lyases cleave heparin/HS by a beta elimination mechanism. This action generates an unsaturated double bond between C4 and C5 of the uronate residue. The C4-C5 unsaturated uronate is termed ΔUA or UA. It is a sensitive UV chromaphore (max absorption at 232 nm) and allows the rate of an enzyme digest to be followed as well as providing a convenient method for detecting the fragments produced by enzyme digestion.
Chemical
Nitrous acid can be used to chemically de-polymerise heparin/HS. Nitrous acid can be used at pH 1.5 or at a higher pH of 4. Under both conditions nitrous acid effects deaminative cleavage of the chain. At both 'high' (4) and 'low' (1.5) pH, deaminative cleavage occurs between GlcNS-GlcA and GlcNS-IdoA, all be it at a slower rate at the higher pH. The deamination reaction, and therefore chain cleavage, is regardless of O-sulfation carried by either monosaccharide unit.
At low pH deaminative cleavage results in the release of inorganic SO4, and the conversion of GlcNS into anhydromannose (aMan). Low pH nitrous acid treatment is an excellent method to distinguish N-sulfated polysaccharides such as heparin and HS from non N-sulfated polysacchrides such as chondroitin sulfate and dermatan sulfate; chondroitin sulfate and dermatan sulfate being un-susceptible to nitrous acid cleavage.
Further Reading
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