Coccidioidomycosis, more commonly known as Valley Fever (VF), is an invasive fungal infection that is endemic to the warm, dry climate found in the Southwestern United States, Infection occurs when airborne spores of the pathogen enter the lungs. The estimated annual incidence of this illness in the U.S. is about 150,000 cases per year. Although about 60% of coccidioidomycosis cases are asymptomatic, the remaining 40% of patients manifest symptoms including self-limiting sore throat, fever, cough, fatigue, and chest pain, with some patients progressing to debilitating, life-threatening disseminated disease. The self-limiting symptoms can persist for weeks or months resulting in a substantial morbidity cost due to work lost and the costs of follow-up physician appointments. Moreover, the annual economic burden in California alone from hospitalizations due to coccidioidomycosis is on average about $190 million and the associated mortality rate for those patients hospitalized is 8%. Recently, Amplyx Pharmaceuticals has in-licensed the entire portfolio of potent Gwt1 inhibitors from Eisai. Several of these compounds show 1) good potency (M100 ⤠0.13 µg/mL) vs. both C. immitis and C. posadasii; 2) over 45% orally bioavailability in mouse and rat models; 3) low potential for drug-drug interactions based on in vitro P450 assays; 4) no observable toxicity at plasma levels in rodents that should permit strong antifungal activity; and 5) strong i vivo efficacy data. We plan to leverage the extensive structure- activity relationships (SAR) elucidated by the chemistry team at Eisai to refine the properties of our "hit" compounds employing the following Specific Aims: Aim 1. Create a first generation library of at least 25 analogues of hit compounds from Phase I. Aim 2. Characterize and select compounds for advancement by employing in vitro assays to assess 2a) antifungal potency; 2b) target engagement; 2c) cytotoxicity; 2d-2i) in vitro PK/PD. Aim 3. Characterize and select compounds for advancement by employing in vivo studies to assess a) PK; b) maximum tolerated dose; c) reduction of fungal burden; d) improved survival in VF models.
Public Health Relevance Statement: Public Health Relevance: Coccidioidomycosis, commonly known as Valley Fever, is an emerging fungal disease in the southwestern United States. Once the disease has progressed, it causes substantial morbidity with an annual burden of $190 million in health care costs in California alone, and has an associated 8% mortality rate of patients who are hospitalized. Current treatments are generally not curative so better therapeutics are urgently needed to treat this disease.
Project Terms: Accounting; American; Amino Acid Sequence; Amphotericin B; analog; Antifungal Agents; Appointment; Area; Arizona; base; Biological Assay; Biological Availability; Breathing; California; Cell Adhesion; Cell Survival; Cell Wall; Central America; Chemistry; Chest Pain; Climate; Coccidioides; Coccidioides immitis; Coccidioides posadasii; Coccidioidomycosis; cost; Coughing; Cytochrome P450; cytotoxicity; Data; desert fever; Disease; Dose; Drug Interactions; Drug Kinetics; Economic Burden; Enzymes; Fatigue; Fever; Fluconazole; follow-up; Fungal Proteins; fungus; Generations; Goals; GPI Membrane Anchors; Health Care Costs; Home environment; Hospitalization; Human; improved; In Vitro; in vitro Assay; in vivo; Incidence; Industrial fungicide; Infection; inhibitor/antagonist; Libraries; Licensing; Life; Lung; Mammalian Cell; Maximum Tolerated Dose; Modeling; Morbidity - disease rate; mortality; mouse model; Mus; Mycoses; New Mexico; novel; novel therapeutics; Oral; Organism; pathogen; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; phase 1 study; Physicians; Plasma; Population; prevent; Process; Property; Proteins; public health relevance; Rattus; Relapse; Reproduction spores; Resistance; Rodent; Role; screening; Sore Throat; South America; Southwestern United States; Structure-Activity Relationship; Surface; Symptoms; Texas; theories; Therapeutic; Toxic effect; United States;
