Inspire Pharmaceuticals, Inc. - Science & Technology

URIDINE TRIPHOSPHATE - A naturally occurring compound that has been shown to activate the P2Y2 receptor.

AGONIST - A chemical substance that activates ("turns on") certain activities in a cell by binding to and activating a receptor.

ANTAGONIST - The opposite of an agonist is an antagonist, which is a chemical substance that blocks or reduces ("turns off") certain activities in a cell by blocking the receptor.

P2Y RECEPTOR - P2Y receptors are protein molecules expressed on the surface of cells. Receptors bind specific types of molecules called ligands (large number of marketed drugs are receptor ligands). This binding activates specific processes within the cell. A simple way to think of a drug binding to a receptor is the analogy of a key fitting a lock. A drug (a key) binds to a receptor (a lock) and activates specific processes within the cell. Inspire's drug candidates bind to a particular type of receptor called the P2Y2 receptor (one type of P2Y receptor) and activate the processes of mucosal hydration and mucociliary clearance.

MUCOCILIARY CLEARANCE - The process by which mucosal surfaces such as the lungs and sinuses are cleared of particles such as dust, bacteria and viruses by the action of cilia. Cilia are small, hair-like projections that move in a waving motion to "sweep" debris away from the mucosal surface. The cilia are suspended in a layer of fluid, which allows them to move freely. Both the fluid layer and the movement (or beat) of the cilia are essential for the health of mucosal surfaces such as the lungs and sinuses.

SCREENING - Testing chemical compounds through the use of various assays to determine whether they have the characteristics desired or needed for pursuing further as a drug candidate.

P2Y RECEPTOR SUBTYPES - P2Y refers to a particular family of receptors, of which at least 8 subtypes (family members) have been identified (P2Y2 is one subtype of this family). The functional activity of many of the subtypes has been demonstrated, and may prove important in the development of new therapies. For example, the P2Y12 subtype has been shown to be important in regulating platelet aggregation - the process that causes blood to clot.

CLONING - The process to produce multiple, exact copies of a single gene. Genes can then be inserted into cells to express their gene products (receptors, enzymes, etc.) to study their function or to use them as drug discovery tools.

Introduction to Inspire Technology
Inspire's original technology was licensed from the University of North Carolina (UNC) in 1995. Research conducted by UNC's group at the Cystic Fibrosis Research Center led to the discovery that UTP, an agonist for the P2Y2 receptor, is capable of increasing airway surface hydration and improving mucociliary clearance. Inspire licensed the rights to UTP for the treatment of lung disease, as well as the rights to assays that allow screening for other potentially useful P2Y2 agonists. At that time, P2Y receptors and their biological activity were just beginning to be understood, with a new P2Y receptor subtype being discovered nearly every other month. To date, at least eight P2Y receptors have been cloned and their activities clearly demonstrated. <Deeper Science on extracellular nucleotides>

NUCLEOTIDE - A molecule of structure similar to building blocks of nucleic acids (DNA and RNA). Nucleotides via interaction with specific receptors stimulate various processes within the cell.

HIGH THROUGHPUT SCREENING - A method for testing a large number of molecules for biological activity in very rapid fashion.

AGONIST - A chemical substance that activates ("turns on") certain activities in a cell by binding to and activating a receptor.

ANTAGONIST - The opposite of an agonist is an antagonist, which is a chemical substance that blocks or reduces ("turns off") certain activities in a cell by blocking the receptor.

NUCLEOTIDE SYNTHESIS - The creation of molecules of structures similar to the "pieces" that make up RNA and DNA. These molecules by their actions on specific receptor proteins stimulate various processes within the cell.

Inspire scientists, working with UNC researchers, immersed themselves in this emerging field, and were soon recognized as leaders in the discovery and synthesis of nucleotides that activate the P2Y2 receptor. Shortly after the initial technology was licensed in, Inspire developed the first high throughput screen for P2Y receptor agonists and antagonists. <Deeper Science on Inspire's screening assay> Inspire currently uses this assay for screening of small numbers of chemicals, and has transferred the assay to contract laboratories for conducting high throughput screening with larger chemical libraries (i.e., > 100,000 compounds), and for screening that is not related to Inspire's core chemistry capabilities.

Inspire scientists have patented many discoveries relating to P2Y2 receptors, their agonists, and their potential importance in the treatment of diseases involving deficiencies in the body's natural mechanisms for protecting mucosal surfaces such as the lungs, eyes and sinuses. In addition, Inspire is continuing to build on original technology by applying expertise in nucleotide synthesis to applications of other P2Y receptor subtypes, such as P2Y12, and to programs aimed at non-P2Y targets as well.

RECEPTOR ACTIVATION - Receptors attract certain types of molecules, called ligands, and bind to them. This binding activates, or "turns on" certain processes within the cell. If a molecule is able to "turn on" activities to the same extent as the native ligand (the ligand that occurs naturally in the body and normally activates the receptor), the molecule is said to "fully activate" the receptor.

NUCLEOTIDE - A molecule of structure similar to building blocks of nucleic acids (DNA and RNA). Nucleotides via interaction with specific receptors stimulate various processes within the cell.

URIDINE TRIPHOSPHATE - A naturally occurring compound that has been shown to activate the P2Y2 receptor.

MUCOSAL HYDRATION - The process by which the body moistens and lubricates mucosal surfaces such as the eyes, sinuses and lungs. Specific cells on mucosal surfaces facilitate the movement of fluids (e.g., water, mucin and lipids) onto these surfaces. Proper hydration of mucosal surfaces is essential for the health of the mucosal tissues.

AGONIST - A chemical substance that activates ("turns on") certain activities in a cell by binding to and activating a receptor.

ANTAGONIST - The opposite of an agonist is an antagonist, which is a chemical substance that blocks or reduces ("turns off") certain activities in a cell by blocking the receptor.

Understanding P2Y2 Nucleotide Receptors and Agonists
When Inspire began operations in 1995, the field of P2Y nucleotide receptors was just beginning to be explored. The P2Y2 receptor, one subtype of the P2Y receptor family, was the first of this family of receptors to be fully activated by a nucleotide, UTP. <Deeper Science on nucleotide therapeutics> This finding - that the nucleotide UTP is an agonist for the P2Y2 receptor - opened the possibility for a new class of drugs - nucleotides - for treating diseases relating to the cellular processes activated by the P2Y2 receptor, such as mucosal hydration and mucociliary clearance.

RPE - The cellular tissue that lines the back of the eye, directly behind the retina.

Since this discovery, Inspire scientists have systematically mapped the location of P2Y2 receptors throughout the body to look for new therapeutic applications. In doing this, Inspire has found that P2Y2 receptors are present on all of the body's mucosal surfaces, including the lungs, eyes, upper airways, mouth, vaginal tract and gastrointestinal tract.

ENDOGENOUS - Naturally occurring.

LOCALLY - At the site where the drug is administered.

SYSTEMIC - Affecting systems throughout the body.

DINUCLEOTIDE - A new class of nucleotides that have a dumbbell-like structure with nucleosides on the ends connected by a phosphate backbone.

NUCLEOTIDE - A molecule of structure similar to building blocks of nucleic acids (DNA and RNA). Nucleotides via interaction with specific receptors stimulate various processes within the cell.

In parallel with mapping the P2Y2 receptors throughout the body, Inspire scientists developed extensive expertise in the synthesis of nucleotides that activate this receptor (receptor agonists). Nucleotides are excellent drug candidates. They are endogenous substances, and, as such, their safety and toxicological profile is essentially benign. They are cleared from the body (metabolized) through normal biological processes, and are metabolized to a great extent locally, which minimizes systemic side effects. In addition, Inspire has developed potent dinucleotides that are remarkably stable. Lastly, the receptors in the body that are activated by nucleotides and dinucleotides are widely expressed and present enormous opportunity in terms of the number and variety of potential therapeutic applications. <Deeper Science on dinucleotides>

CILIATED EPITHELIAL CELLS - A type of cell that lines and protects various surfaces of the body. The cell has hair-like projections called cilia that move in a sweeping motion to cleanse and protect the cell surface.

GOBLET CELLS - A type of epithelial cell that secretes mucin - a viscious, slippery fluid that moistens and protects the cell surface. Goblet cells are named for their shape, which resembles a drinking goblet - wide and open at one end.

TYPE II ALVEOLAR CELL - An airway cell that is important for gas exchange in the lungs and airways.

P2Y2 Receptors in the Lungs and Upper Airways
The P2Y2 receptor coordinates the entire mechanism of mucociliary clearance in the upper and lower respiratory tract. This process can be regulated therapeutically by the local delivery of molecules that bind to and activate the receptors. Studies have established that P2Y2 receptors are found on each of the three principal cell types that line the airways: ciliated epithelial cells; goblet cells; and Type II alveolar cells. On activation of the P2Y2 receptor on ciliated epithelial cells, salt and water are released from the cell, mucous secretions are hydrated, and ciliary beat frequency is increased. Activation of the P2Y2 receptor on goblet cells modulates the release of mucin. When the P2Y2 receptors on Type II alveolar cells are activated, they release surfactant, a lubricating molecule that maintains the surface tension of the smallest peripheral airways and prevents their collapse.

EPITHELIAL CELL... ...cilia beat faster ...chloride and water transport hydrates airways	GOBLET CELL... ...releases mucin	TYPE II ALVEOLAR CELL.. ...surfactant release maintains patency of small distal airways
P2Y2 receptors are present on three types of human airway cells: respiratory epithelial cells, goblet cells and type II alveolar cells.

The ability to activate mucosal hydration and mucociliary clearance in the lungs and upper airways provides opportunities for the treatment of serious disorders including cystic fibrosis, a fatal genetic disease, as well as upper respiratory disorders that involve nasal symptoms such as congestion, pressure and nasal blockage. Such disorders include rhinosinusitis, allergic rhinitis and upper respiratory infections including the common cold and influenza. In addition, increasing mucociliary clearance in the lungs allows for non-invasive collection of mucus samples from the lungs which may be beneficial in the diagnosis of lung cancer.

RPE - The cellular tissue that lines the back of the eye, directly behind the retina.

AGONIST - A chemical substance that activates ("turns on") certain activities in a cell by binding to and activating a receptor.

CONJUNCTIVAL MUCOSAL SURFACE - The cellular tissue on the outer surface of the eyeball and inner surface of the eyelids.

INTRAVITREALLY - Into the clear, jelly-like fluid that fills the back of the eye (posterior chamber) behind the lens.

RETINAL DETACHMENT - A condition that occurs when the retina (the sensory membrane that lines the back of the eye and is connected to the brain by the optic nerve) pulls away from the underlying tissue (the retinal pigment epithelium). The resulting space fills with fluid, and vision may be impaired.

P2Y2 Receptors in the Eye
In parallel to the respiratory program, Inspire scientists demonstrated that P2Y2 receptors are present on the ocular surface and conjunctiva of the eye. Inspire began uncovering new therapeutic uses for next generation P2Y2 agonists, such as treating dry eye. This work included ground-breaking biology that demonstrated for the first time that the conjunctival mucosal surface was capable of secreting therapeutically significant amounts of fluid and tear components to the ocular surface when stimulated with diquafosol tetrasodium.

<Deeper Science on new discoveries in nucleotide release, metabolism and re-uptake>

Page last updated: 27-Nov-2006