Sugars in Medicine

Anti-cancer agents are molecules that kill cancer cells. Cancer comprises numerous different diseases characterized by abnormal and/or uncontrolled cell growth. This cell growth may be triggered by external (e.g., chemicals, radiation, viruses) and internal (e.g., hormones, immune conditions, inherited mutations, stress) factors. There are three general cancer classifications: (1) carcinomas, cancers originating in the epithelial tissue; (2) sarcomas, cancers originating in connective tissue and muscle; and (3) gliomas, cancers originating in nerve tissue. Some 10,000,000 Americans have or have had cancer, and an estimated 1,400,000 new cancer cases were diagnosed in 2006 in the U.S. Of these, over 560,000 Americans and 6,000,000 people worldwide will die of cancer this year. Lung (162,460 estimated U.S. deaths in 2006), colon and rectum (55,170 deaths), breast (41,430 deaths), and prostate (27,350 deaths) are prevalent cancers. Antineoplastic agents, which prevent the development, maturation, and spread of cancerous cells, are used along with surgery and radiation to treat cancer.

For decades, cancer drug research has focused on the cytotoxic drugs; ‘biological poisons’ that can induce the death of the cancer cells with minimal effect on normal cells. These drugs include compounds with multiple effects, such as DNA-modifying agents like cisplatin, as well as drugs that interfere very precisely with defined physiological processes such as microtubule polymerization (e.g., paclitaxol), metabolite synthesis (e.g., 5-fluorouracil), and chromosome topology (e.g., topotecan). The term ‘neocytotoxics’ has been coined to refer to newer drugs that act on essential proteins but in novel ways; e.g., cyclin dependent kinase inhibitors that target cell division and proteosome inhibitors that affect protein turnover. Some cytotoxic drugs contain a sugar that is known to be vital for the drug’s activity; e.g., bleomycin, doxorubicin and etoposide. Modification of the structure of the sugar has led to improved cancer drugs, such as epirubicin, an analog of doxorubicin in which the stereochemistry of the aminosugar has been changed. Centrose is pursuing several research programs that aim to discover new cytotoxic cancer drugs through sugar modification.

Toxicity though is still one of the major issues when developing new anticancer agents. Researchers try to avoid widespread toxicity, focusing on drugs that inhibit only those functions unique to cancerous tissue. Yet this ideal has not yet been met for any current cancer therapeutic, although antibody–based or targeted therapies come close. Centrose has discovered new anticancer leads that have measurably reduced toxicity.

A recent revolution in cancer therapy involves the discovery and use of drugs targeted to special features of cancer cells that endow them with the traits of cancer such as uncontrolled growth, evasion of programmed cell death and ability to spread into surrounding tissues. A popular type of drug is one that inhibits kinases of key signaling pathways, which might not be essential in normal adult cells but are commonly over-abundant or over-active in certain cancer cells. Inhibition of the function of such targets is expected to provide more effective and less toxic cancer drugs than the traditional cytotoxic agents. This hope has been amply supported by the impressive therapeutic behavior of the initial drugs of this type such as Gleevec, Iressa and Tarceva that inhibit kinases in cell signaling pathways responsible for cancer. Centrose is also pursuing studies of a new type of targeted cancer drug whose activity is greatly influence by the structure of the attached sugar.

A special class of cancer drug involves the use of antibodies to unique epitopes on cancer cells that like the drugs targeted to cell signaling pathways, affect cancer cells specifically and spare normal cells. Herceptin for treatment of breast cancer and Avastin for treatment of colorectal cancer are recently approved drugs of this type. The specificity and potency of some antibodies is dependent upon sugars attached during formation of the protein. Drug researchers are just beginning to develop ways to manufacture antibodies with the necessary sugars. The cancer cell specific antibodies may also carry potent toxins (small molecules or proteins) that if delivered into the cell with the antibody can produce a cancer cell specific toxicity. Mylotarg (gemtuzumab ozogamicin) is the first approved drug of this class.

Anti-infectives agents are molecules that kill organisms that can lead to infection. Despite the early successes of anti-infective drug discovery, infectious diseases remain the second-leading cause of death worldwide. For most infectious diseases, the pace of drug resistance has dramatically outpaced the discovery of new drugs - particularly anti-infective drugs with novel mechanisms of action. Innovative drug discovery platforms, such as the ones provided by Centrose (see Technology Platform), are essential to jump-start and sustain the world's anti-infective pipeline.

Bacterial infections cause 17,000,000 deaths globally, particularly in children and the elderly. Within the U.S., roughly 2,000,000 people in U.S. hospitals acquire bacterial infections annually from which nearly 90,000 of them die (70% resulting from resistant organisms). Sugars are a critical element of many frontline antibiotics. For example, the saccharides attached to macrolide antibiotics (e.g. erythromycin) are essential to targeting these drugs to the bacterial ribosome and alterations of macrolide sugar patterns in latter generation macrolides contribute to circumventing bacterial resistance and/or their enhanced absorption, distribution, metabolism, and excretion (ADME). Likewise, modification of the sugars components of glycopeptide antibiotics (e.g. vancomycin - often referred to as ‘an antibiotic of last resort’ for life-threatening multi-resistant bacterial infections) has lead to next generation analogs which display both broader spectrum, enhanced ADME and/or most notably, the ability to target vancomycin-resistant bacteria. Other antibiotics, such as the aminoglycosides, are almost completely sugar-derived.

Over 400 pathogenic viruses that infect humans have been identified and there exists the constant threat of newly emerging viruses, such as SARS-CoA or avian flu and many are becoming drug resistant. As an indication of the potential impact of emerging viruses, the best death toll estimates of the next influenza pandemic range from 2 to 50 million with tens of millions requiring medical attention. While only a few major classes of antiviral drugs are currently available, sugars are a core element in antiviral drug development. For example, the core scaffolds of most nucleoside inhibitors (e.g. AZT) are carbohydrates or carbohydrate mimics. The neuraminidase inhibitors (e.g. Tamiflu® or Relenza®) also mimic sugar structure and target a carbohydrate-processing event vital to viral coat maturation.

Among the many opportunistic infections, systemic fungal infections are becoming increasingly common in hospital settings. Patients most at risk include transplant and chemotherapy patients, HIV patients, elderly patients and patients with compromised immune systems. Some of the most common blood-borne fungal infections include aspergillosis, candidiasis and cryptococcosis. Here again, sugars are a key therapeutic element. Specifically, of the frontline antifungal drugs, the polyenes (e.g. amphotericin) are absolutely dependent upon an attached aminosugar for both molecular mechanism and ADME.

Parasitic diseases also take an enormous toll on human health, particularly in tropical regions, and, in conjunction with tuberculosis, currently contribute an estimated 5% of the total global disease burden. Among the existing antiparasitic drugs, the avermectins (originally used as antihelmenthics) are now in clinical use for the control of onchocerciasis, stongyloidiasis and lymphatic filariasis and structurally contain two attached sugar residues.