Boucher, Richard C. Compound/Combination Selection Core (Core E) A. Description of the Core. Table 1. Summary of test agents The pathogenesis of CF and COPD lung disease is multi-factorial, but Class Agent Name includes a common disease-initiating step: the reduction of mucociliary Mucus Hypertonic saline clearance (MCC). Based on studies shaping the foundation of the tPPG Hydrators Mannitol Projects I and II, it has been observed that normal mucus clearance ENaC modulators requires adequate hydration of the ainway surface (see Program Overview). However, both CF and COPD patients exhibit an increase in Reducing N- acetylcysteine ainway mucus concentration (% solids), as a result of reduced ainway Agents Nacystelyn DTT (and derivitives) hydration, due to CFTR dysfunction (1), mucin hypersecretion (2), or a Erdosteine combination of the hwo. The result is the appearance of ainway-adherent GILT mucus plaques and the slowing of both cilial- and cough-dependent mucus clearance, leading to chronic ainway infections. Therefore, developing Mucus Azithromycin therapies to enhance the clearance of mucus from the ainways is likely to Expression Cempra Modifiers Gilead benefit patients with CF/COPD. The primary goal of Core E is to support all the Projects of the tPPG by identifying the most effective therapeutic Surfactants/ Lucinactant agents to enhance the dis-adherence and transportability of mucus. Detergents DPPC As part of this tPPG project, we have identified a number of classes of Survanta Tyloxapol candidate therapeutic agents, which are predicted to alter the properties of TweenSO mucus, facilitating its clearance. These classes and examples of potential agents are summarized in Table 1. Other Ca^* Chelators Because the viscoelasticity of mucus is concentration dependant, agents Mucolytics Low MW heparin Dextran which increase the hydration state of mucus (called hydrators) will be Bicarbonate studied (3). This will include osmolytes (such as hypertonic saline and Hyaluronic acid mannitol) as well as modifiers of ENaC-mediated fluid reabsorption, Test Agent Class including: ENaC blockers (Parion P552 and PI 527) and modifiers of ENaC Modihers of Modifiers ol Mucus Mucus activity (QUB and SPLUNK). As an alternative approach to reduce mucus Visco(?tc!5ticitv Concentration concentration, we will also evaluate the use of macrolides, which have been Mucolytics/ shown to reduce mucus expression (4). As well as Azithromycin, we will test a series of novel macrolide agents from Cempra and Gilead which are optimized to improve their activity (see Letters of Support). In addition to lowering the concentration of mucus, we will also seek to identify agents which reduce its viscoelasticity and adhesivity, by altering mucin-mucin and mucin-protein interactions. Di-sulfhydryl reducing agents are predicted to decrease the viscoelasticity of mucus by decreasing the head-to-tail chaining of mucin monomers. In addition to existing reducing agents (e.g. N-acetylcysteine and DTT) we will also test novel reducing agents such as Gamma-interferon-inducible lysosomal thiol reductase (GILT) from Dr. Peter Cresswell (Yale) and a variety of novel recombinant- DTTs (DTT-Rs) from Parion which increase the efficiency and duration of action (see Program

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