Broadly protective (universal) virus-like particle (VLP) based influenza vaccine
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AbstractDESCRIPTION (provided by applicant): A safe and effective therapeutic for treatment of osteoarthritis (OA) represents a major unmet medical need. OA is the leading cause of disability in the US and pain is a predominant clinical feature. However, chronicuse of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with potentially life-threatening gastrointestinal bleeding and calculations estimate that about 100,000 patients are hospitalized annually for NSAID related GI complications and about 16,500 NSAID-related deaths occur among arthritis patients in the US each year, leading to 2 billion in health care costs. The goal of this proposal is to develop a novel therapeutic approach based a new molecular mechanism that targets a key molecule involved in nociceptive signaling from the joint. We propose to develop a novel, first-in-class therapeutic small molecule compound which is a functional antagonist of TRPA1 (Transient Receptor Potential, Subfamily A, member 1) for the treatment of OA pain. TRPA1-receptor/channels serve a highly specific function on sensory nerve fiber endings in the joint that detect and transmit the sensations of pain and hyperalgesia in response to inflammation and nerve injury. Since TRPA1 is one of the most important signal integrators for pain in sensory nociceptors in the joint, an antagonist of TRPA1 will function as a peripherally acting analgesic. Our innovative approach is based on development of novel therapeutic agent that will block nociceptive signals at the firststage of neural processing and does not involve CNS action. Algomedix employs a rational pharmacology approach and has already made substantial progress in the identification of novel, small molecule chemical antagonists of TRPA1 The long-term goal of this project is to identify orally available antagonists of TRPA1 that will block the excitation of the nociceptive afferent fibers present in the joint that are activated in OA. This approach is based upon genetic and in vivo pharmacologic evidence that modulation of TRPA1 activity will have therapeutic value. The aims are: AIM 1 will be to synthesize a group of 75 novel, structural analogs based upon newly discovered TRPA1 ligands using a novel scaffold. Synthetic medicinal chemistry and structure guided drug design efforts will be used to enhance lead potency and to further define structure-activity relationships (SAR). AIM 2 will be to define the potency and pharmacological of novel compounds on human and rat TRPA1. In AIM 3, the pharmacological selectivityfor novel antagonists will be defined among members of the TRP superfamily using a panel of related TRP channels, including TRPV1, TRPV3, TRPM8 and several TRPC members. AIM 4 will pharmacologically characterize the activity of the new drug using cultureddorsal root ganglion neurons, which are the primary target cell for TRPA1, and AIM 5 will conduct in vitro ADME profiling for the top-ranked active compounds and determine pharmacokinetics using oral dosing. The final Phase 1 milestone is to deliver an advanced lead molecule and backup compounds that have all properties necessary for nomination to a full development program in Phase 2. The anticipated Phase 2 program will consist of animal efficacy testing in multiple OA models and conducting pharmacokinetic studies in multiple animal species using oral dosing to enable the filing of an IND. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: A safe and effective therapeutic for the treatment of osteoarthritis (OA) presents a major unmet medical need for 50% of people in the US over 65 years of age. While pain is a predominant clinical feature of OA, chronic use of NSAID therapeutics present significant safety concerns due to life-threatening gastrointestinal complications. Thus, there is a need todevelop small molecule drugs directed to novel targets that are involved in pain transduction in OA and that are expected to have fewer adverse effects than those drugs currently available. Transient Receptor Potential Channel, subfamily A, member 1 (TRPA1) is such a target and is the focus of this proposal. The overall objective of this research is to identify and develop a novel, small molecule therapeutic drug which modulates the activity of the TRPA1 receptor-channel. TRPA1 receptor/channels play a highly specific function in sensory nerves in the joint that transmit the sensations of pain and hyperalgesia in response to inflammation as well as joint disease. Since TRPA1 is one of the most important signal integrators for pain in sensory nociceptors, targeting TRPA1 is a novel approach to block nociceptive signals at the first stage of neural processing. A TRPA1 antagonist will function as a peripherally acting analgesic and is designed to be without adverse CNS effects. Algomedix employs an innovative rational pharmacology approach which has proven capable of identification of multiple new TRPA1 ligands. Starting with novel antagonists of TRPA1 discovered at Algomedix, this proposal will lead to the identification of a molecule suitable for advancement toa full development program. It is anticipated that a pain medicatio
* information listed above is at the time of submission.