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Addressing Unmet Medical Needs with Complex Carbohydrate Chemistry
Find out how carbs are being used to develop a range of complex therapeutic molecules and drugs.
Carbohydrates have been shown to play a fundamental role in normal cell functions as well as in major disease pathologies including cancer, cardiovascular disease, and inflammatory diseases. As a class of molecules, carbohydrates have an enormous range of shape, orientation and composition. Due to this structural diversity, carbohydrate chemistry can be applied to develop a broad range of complex therapeutic molecules and drugs, including pure carbohydrates as well as protein-linked carbohydrates, or glycoproteins. However, as a consequence of their structural complexity, carbohydrates have not received as much scientific attention as nucleic acids and proteins. However, significant progress is being made in this area.
Consider diabetes mellitus, a condition shared by nearly 26 million Americans and growing, according to the U.S. Centers for Disease Control and Prevention. As uncontrolled diabetes can lead to micro- and macrovascular complications, tighter but safe glycemic control is imperative. Interestingly, even as high carbohydrate intake can lead to a rise in blood sugar (glucose) and increase one’s risk of diabetes, research suggests that complex carbohydrate chemistry is one key to reducing the uptake of sugar into the bloodstream.
A nonsystemic, nontoxic chewable complex carbohydrate-based compound is being studied for its ability to reduce post-meal elevation of blood glucose, and thus as a treatment to slow the onset of type 2 diabetes and related complications such as heart disease, stroke, kidney damage, retinopathy, and diabetic foot. The compound is a complex polysaccharide designed to be taken before meals and works in the gastrointestinal tract to block the action of carbohydrate-hydrolyzing enzymes that break down carbs in foods during digestion, reducing the amount of available glucose absorbed through the intestine. Manchester, NH-based Boston Therapeutics developed this treatment under the name PAZ320 and it is currently being tested in clinical trials.
Necrosis and Ischemia
A separate potential application of carbohydrate chemistry is as an injectable antinecrosis drug, both for the prevention of necrosis and the treatment of ischemic conditions that may lead to necrosis. The drug consists of a stabilized glycoprotein composition contain oxygen-rechargeable iron, targeting both human and animal tissues and organ systems deprived of oxygen and in need of metabolic support.
Necrosis is the outcome of severe and acute injury. It is involved in many pathological conditions such as heart attack, brain injuries and stroke, neurodegenerative diseases such as Alzheimer’s dementia, Lou Gehrig’s disease (ALS), septic shock, liver cirrhosis, chronic hepatitis, pancreatitis, diabetes, acute or critical limb ischemia, gangrene, chronic pressure ulcers, and many others. Necrosis occurs following ischemia (a shortage of oxygen supply to the tissue due to restriction in blood supply). The only treatment available at present for necrosis is providing oxygen by a high pressure facility. Thus, there is a crucial need to develop drugs for prevention and treatment of this pathology.
For decades, oxygen carriers have been developed for perfusion and oxygenation of ischemic tissue; none have yet succeeded. These products were either blood-derived elements, synthetic perfluorocarbons, or red blood cell modifiers. Several of the hemoglobin-based oxygen carriers (HBOC) contained nonfunctional methemoglobin impurities. These products failed to secure FDA approval based upon either poor outcomes in clinical trials or poorly formulated product.
The new approach to treatment of ischemic tissue and prevention of necrosis is fundamentally different; it is a new chemical entity (NCE), not a biologic blood substitute, with a modified Heme chemical structure. The new compound prevents methemoglobin formation associated with the adverse effects of vasoconstriction and myocardial infarction. Furthermore, because of its extremely small molecular size—roughly 1/5,000th the size of a red blood cell—it is able to perfuse constricted, ischemic capillaries that are inaccessible to red blood cells. This small molecular size has particular significance in treating vascular complications of diabetes since red blood cells may already be enlarged and lower limb vasculature may be compromised.
One such complication is limb ischemia, a chronic condition of severe obstruction of the peripheral circulation that results in severe pain in the extremities; lower-limb ischemia is a life-threatening complication for patients with poorly controlled diabetes and affects 10 percent of the diabetic population. The new compound is a glycoprotein-derived substance that is sourced from a biological mixture, which is prone to immunologic activity, and the agent is purified by a novel processing technology. In general, the human body conserves the protein and recaptures amino acid moiety. The compound is broken down and eventually is collected in the spleen or liver, or it is simply eliminated by reversible endocytic processes in the kidneys.
A veterinary facsimile of this compound is also under development, due to an unmet need in this market for blood replacement and oxygen delivery to damaged or ischemic tissue due to trauma, surgery anemia, and other disease conditions. This can serve as an oxygen delivery mechanism for animals suffering ischemia or traumatic and surgical blood loss events.
IBD and GI Inflammation
A further potential application of novel carbohydrate chemistry, also in the development stage, involves a formulation containing fractionated pectin for blocking inflammation in the gastrointestinal (GI) tract. Several chronic diseases, such as type 2 diabetes, metabolic syndrome, and cardiovascular diseases, have been shown to be associated with inflammation attributable to increases in tumor necrosis factor alpha (TNF-α), Interleukin-6 (IL-6), and C-reactive proteins, in addition to others. Furthermore, evidence strongly supports a link between inflammatory bowel disease (IBD) and various medical indications.
It has been shown that pectin, a plant-derived carbohydrate, has a favorable effect on a broad range of pathological conditions. In IBD, pectin might aid in decreasing the inflammatory response in the colon by moderating the amounts of proinflammatory cytokines and immunoglobulins, and might work to reduce inflammation in a dose-dependent manner. Consequently, a new carbohydrate chemical structure is being developed; the polysaccharide compound has been shown to bind to TNF-α and thereby block immune system activation and inflammation. The compound is being designed as a dietary supplement to support colon health.
In summary, complex carbohydrate chemistry is a key tool for addressing unmet medical needs in a variety of areas. Its continued development might offer new treatments and hope for millions of patients worldwide.
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