TORONTO The appearance of drug-resistant pathogens has caused great concern in the medical community. With the emergence of new virulent strains of the bacteria that cause diseases such as pneumonia, meningitis, tuberculosis, bronchitis and malaria, there is an urgent need for novel antibiotics.
GlycoDesign, an emerging biotech company and recognized leader in the field of glycobiology, believes it has the technology platform that will pave the way for the development of a new generation of antibiotics.
Jeremy Carver, president and CEO of GlycoDesign, told BioWorld International the company is taking an entirely new approach to designing antibacterial drugs. The effort is focused on the mechanisms by which certain pathogens successfully establish themselves in human hosts without being detected by the immune system.
There is growing evidence that carbohydrate structures on the surface of cells act as ¿recognition signals¿ that allow communication between cells and the external environment and regulate key cellular functions, such as the growth and mobility of cells, activation of the immune system and cell adhesion.
According to Carver, certain bacteria particularly those that infect via mucous membranes, such as Neisseria gonorrhea and meningitis use molecular mimicry to disguise themselves from the immune system. The molecules involved are carbohydrates known as low-molecular-weight oligosaccharides (LOS), found on the surface membranes of these specific types of bacteria. The oligosaccharides mimic carbohydrates on the surfaces of human glycoproteins and glycolipids, using them as a ¿cloak¿ to evade the body¿s immune response, thereby allowing the bacteria to invade and proliferate. Evidence for this mechanism of action has been shown in studies on mutant bacteria which revealed that their absence in N. gonorrhea can suppress infection.
Since bacterial glycosyltranferases are the enzymes responsible for the production of the LOS, they are an obvious target for therapeutic intervention as a potential way to ¿uncloak¿ the bacteria, rendering them visible to attack by the body¿s defense mechanisms, Carver added.
With this research goal in mind, GlycoDesign has signed a two-year, collaborative research agreement with the National Research Council (NRC) of Canada¿s Institute for Biological Sciences (IBS), of Ottawa, an organization with world-class expertise in carbohydrate chemistry and glycobiology.
IBS is one of five biotechnology-focused research institutes of the NRC. It conducts innovative research in neurobiology and immunochemistry of importance to the health and pharmaceutical sectors. Research programs are typically carried out with partners in industry, universities, hospitals and other research and development organizations.
IBS¿ immunochemistry program conducts molecular-level research leading to the development of improved diagnostic agents, vaccines and immunotherapeutics. The program¿s main focus is the immunochemistry of carbohydrates as related to bacterial pathogenesis and vaccine design. It is pursued through research groups devoted to glycobiology, novel antibodies, pathogenesis and vaccine design. This expertise will be used to help identify new drug candidates for GlycoDesign¿s infectious disease program.
IBS, under the terms of the research agreement, will undertake to clone and express a range of bacterial glycosyltranferases. GlycoDesign will then use these enzyme targets and attempt to find carbohydrate processing inhibitors (CPIs) to block LOS synthesis.
CPIs are small-molecule, orally active inhibitors of enzymes which are responsible for the synthesis of the key carbohydrate structures involved in disease. These CPIs block enzymes that process carbohydrates, thereby modifying the structures found on the cell or pathogen surface. This changes the cell¿s or pathogen¿s response to signals in a predetermined way. For example, GlycoDesign¿s lead CPI compound, GD0039, which is in Phase II trials for renal cell cancer, blocks the synthesis of the invasion-specific carbohydrate on tumor cells, inhibits the cells¿ growth and stimulates the body¿s immune responses to the tumor.
The search for effective inhibitors of bacterial glycosyltranferases will involve high-throughput screening of the enzymes against large numbers of compounds from the company¿s proprietary directed combinatorial library, Carver said. The best CPI drug candidates will proceed to clinical development.