PATENTED: Drugs targeting IFT proteins
Patent 7,553,674 : Methods of identifying compounds useful for modulating intraflagellar transport . Granted June 30, 2009. full text from USPTO.
Inventors: George B. Witman, Gregory J. Pazour, Joel L. Rosenbaum (Yale faculty), Douglas G.Cole.
Background
It’s the goal of any cell biologist to discover and describe a totally new molecular mechanism or cellular process. Just such a discovery was made during the mid-90s, in the laboratory of Joel Rosenbaum at Yale.
Cross-section of two Chlamydamonas cilia. Click for Wikipedia entry.
Rosenbaum and colleagues were looking at the green algae Chlamydamonas–specifically at the long, slender cilia that project outward from its cell body. Cilia, called flagella in cells that have only one of these structures, are present in many eukaryotic cells and can function both as a type of cellular paddle (as in the case of a swimming sperm cell) or as an antenna, positioned to sense the surrounding environment.
What the Yale researchers saw when they looked carefully inside the cilia, at high magnifications, were tiny granules that were moving along the cilia. What became clear in subsequent experiments is that these particles move back and forth along the cilium, like miniature cargo elevators, to transport proteins and lipids. These cargo include sensory molecules, as well as the building blocks needed to extend the growing structure.
Rosenbaum and colleagues termed this mechanism intraflagellar transport (IFT). Most importantly, though it was discovered in the model green algae cells, IFT is a mechanism that has been exquisitely conserved during evolution. Microscopic parasites and human beings, confronted alike with the necessity of building and maintaining cilia and flagella in many different types of cells, all use the same basic transport molecules, with only minor variations.
As with any molecules so central to diverse cellular functions, when something goes wrong, like an inherited mutation in the gene coding for an IFT protein, severe diseases can develop. In humans, difficulty building and maintaining cilia and flagella contribute to diseases of organs that depend on these structures, like the kidneys, the eyes and the heart during early development
Patent implications
The new patent claims the use, for “diagnostic, screening, and therapeutic” purposes, of 14 key proteins that are present in humans and other organisms with flagella. These proteins are assembled together within the cell to make a multi-molecular machine for transporting cargo in the flagellum. The exact workings of these protein complexes are still poorly understood.
The patent claims any pharmaceutical agent to diagnose or treat a problem with these complexes, or at least those drugs designed to interact with the 14 patented proteins, for uses including to “modulate flagellar function”. Although much of the biomedical research into IFT has been directed at curing human genetic disorders, this patent would also appear to cover the design of any antibiotics targeting the IFT proteins in human parasites, such as Leishmania or Trypanosoma brucei, which rely on their flagella for survival.
The diagnostic claim appears to broaden the scope of the patent in a significant way. Severe diseases resulting from cilia defects, such as Bardet-Biedl syndrome, may not be cured by drugs that target IFT proteins, because there are many other molecules involved. However, a diagnostic test, using IFT proteins to evaluate the “size”, “beating” or “cell motility” of a sample, as is imagined by the authors of the patent, may not be as far-fetched.
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Read this recent New York Times article on ciliary diseases, flagellum research and IFT.
Kozminski, K G, K A Johnson, P Forscher, and J L Rosenbaum. 1993. A motility in the eukaryotic flagellum unrelated to flagellar beating. Proceedings of the National Academy of Sciences of the United States of America 90, no. 12 (June 15): 5519-5523. doi:VL – 90. Download PDF.
