PATENTED: Drugs based on ribosome structure
Update, October 7, 2009: The description of ribosome structure, including the work protected by these patents, was awarded the 2009 Nobel Prize in Chemistry, announced today. A new post discusses the implications.
Patent 7,504,486 : Determination and uses of the atomic structures of the large ribosomal subunit and ribosomal subunits and their ligand complexes. Granted March 17, 2009. full text from USPTO.
This is the most recent from a set of similar Yale patents, most importantly: Patent 6,638,908: Crystals of the large ribosomal subunit. Granted October 28, 2003. full text from USPTO.
Inventors: Thomas A. Steitz (Yale faculty), Peter B. Moore (Yale faculty), et al.
Background
Ribosomes translate messenger RNA into protein. To accomplish this most basic biological task, at the very center of the “central dogma” of biology, requires a large molecular machine composed of both protein and RNA pieces. The genes coding for these components are among the most evolutionarily conserved (i.e. sharing similar sequences), indicating the ribosome’s essential and highly optimized function. Because of the absolute biological requirement of synthesizing proteins, the ribosome is an attractive target for antibiotics. Designing drugs that inhibit the ribosomes of human pathogens efficiently and specifically is a major goal of ribosome biology.
Our modern understanding of molecular mechanism in the cell comes from x-ray crystallography. This technique relies on x-rays, directed through highly-pure crystals of the molecule to be examined. Based on the structure of the molecular components of the crystal, the x-rays are diffracted into a complex pattern. This pattern may be deconvolved–computationally reconstructed–into a three-dimensional model of the molecule-of-interest, at atomic-scale resolution.
Acquiring these fascinating 3D molecular models is complicated by a number of factors, particularly the difficulty of procuring a sufficiently large, pure sample of the subject molecule. This protein, nucleic acid, etc. must then self-assemble into a highly ordered crystal–a requirement for high-resolution crystallography. RNA, a major component of the ribosome, is notoriously tricky to crystallize and diffract, and the crystallization of the large ribosomal subunit in 2000 (by Steitz and colleagues at Yale) represented a huge breakthrough in our understanding of not only the ribosome, but of the structure of RNA molecules generally–that is, how they interact physically with themselves and other molecules.
Patent implications
A key patent on the work of Steitz, et al., 6,638,908, claims the crystallization of the large ribosomal subunit, from any organism, with attached ligands (drugs), to a resolution of 5 angstroms. Other patents (7,504,486, 6,952,650, 6,947,845, 6,947,844, 6,939,848, 6,631,329) deal with other details of crystallization and methods for identifying “modulators of ribosome function” and protein synthesis, such as antibiotic drugs.
These patents have been licensed by Yale to Rib-X pharmaceuticals, co-founded by Dr. Steitz and Dr. Moore and based in greater New Haven.
