Invasive candidiasis is a disease associated with significant morbidity and mortality, with only 3 classes of antifungals available for treatment. While Candida albicans remains the most common species associated with this disease, other non-albicans Candida species are emerging or growing in prevalence. The global emergence of Candida auris, a species with a high rate of multi-drug resistance capable of nosocomial transmission, and reports of Candida glabrata infections resistant to both azoles and echinocandins, highlight the critical need for new classes of antifungal drugs that can combat resistance and treat invasive fungal diseases. AimMax Therapeutics is developing a novel class of promising antifungal peptides that are differentiated from other antimicrobial peptides in development. Peptides have been considered as promising therapeutics because of their novel mechanisms of action, rapid cidality, low propensity for resistance development and low potential for drug-drug interactions. However, there are certain liabilities associated with historical antimicrobial peptides as systemic therapeutics, including propensity for lysis of human cell membranes causing toxicity and degradation by circulating proteases and peptidases. Our preliminary studies have shown that: 1) several of the AimMax peptides have antifungal activity across Candida species, including activity against resistant strains, 2) this activity is rapidly fungicidal in nature, 3) there is no cell lysis or intracellular cytotoxicity against human cells and they are well-tolerated following repeat dosing in vivo, 4) they are salt tolerant and retain activity under physiological conditions, and 5) they can be modified to increase stability against proteolytic degradation and demonstrate good plasma exposure in vivo. The objective of this proposal is to optimize the peptides by enhancing antifungal activity and microbiological profile, while maintaining safety (no toxicity) and minimizing proteolytic instability and undesirable physicochemical properties. These studies are essential to select potent antifungal peptides to combat resistance and ensure that they are "druggable" for further development. The objectives of the proposal will be achieved by rational peptide design and structure-activity relationship analysis using data from a series of in vitro and in vivo screening assessments. Peptides selected based on pre-determined criteria will undergo expanded evaluations. Together, these studies will form the basis of candidate selection for further development and IND-enabling work in a Phase 2 SBIR application. The ultimate goal of this program is to develop a broad- spectrum antifungal drug that will address the rising threat of drug resistance in Candida species and provide an alternative treatment option for life-threatening invasive candidiasis.
Public Health Relevance Statement: PROJECT NARRATIVE Invasive candidiasis is a significant cause of morbidity and mortality. The emergence of multidrug resistant Candida species highlights the need for new antifungals. AimMax Therapeutics is developing a novel class of antifungal agents for the treatment of serious and life-threatening invasive fungal infections.
Project Terms: Acids; Amines; amine; Antifungal Agents; Antifungal Drug; Therapeutic Fungicides; anti-fungal; anti-fungal agents; anti-fungal drug; antifungals; Arginine; L-Arginine; Azoles; Biological Assay; Assay; Bioassay; Biologic Assays; Candida; Monilia; Candida albicans; C albicans; C. albicans; C.albicans; Candidiasis; Candidosis; Moniliasis; Cell membrane; Cytoplasmic Membrane; Plasma Membrane; plasmalemma; Cells; Cell Body; Centers for Disease Control and Prevention (U.S.); CDC; Centers for Disease Control; Centers for Disease Control and Prevention; United States Centers for Disease Control; United States Centers for Disease Control and Prevention; Chemistry; High Pressure Liquid Chromatography; HPLC; High Performance Liquid Chromatography; High Speed Liquid Chromatography; Disease; Disorder; Drug resistance; drug resistant; resistance to Drug; resistant to Drug; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Erythrocytes; Blood erythrocyte; Erythrocytic; Marrow erythrocyte; Red Blood Cells; Red Cell; blood corpuscles; Goals; Primary carcinoma of the liver cells; Hepatocarcinoma; Hepatocellular Carcinoma; Hepatocellular cancer; Hepatoma; Liver Cells Carcinoma; liver carcinoma; Human; Modern Man; In Vitro; Infection; Microbiology; Morbidity - disease rate; Morbidity; mortality; Mus; Mice; Mice Mammals; Murine; Mycoses; Fungus Diseases; fungal infection; fungus infection; Parents; Peptide Fragments; Esteroproteases; Peptidases; Protease Gene; Proteases; Proteinases; Proteolytic Enzymes; Peptide Hydrolases; Peptides; Pharmacokinetics; Drug Kinetics; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Plasma; Polyenes; Safety; salt; Sodium Chloride; Solubility; chemical structure function; structure function relationship; Structure-Activity Relationship; Testing; Time; Tissues; Body Tissues; Triazoles; United States; Work; Antibiotic Resistance; Resistance to antibiotics; Resistant to antibiotics; antibiotic drug resistance; antibiotic resistant; Core Protein; base; Acute; Clinical; Phase; Physiological; Physiologic; Series; Link; Ensure; Evaluation; Blood Serum; Serum; Multidrug Resistance; Multiple Drug Resistance; Multiple Drug Resistant; Resistance to Multi-drug; Resistance to Multidrug; Resistance to Multiple Drug; Resistant to Multiple Drug; Resistant to multi-drug; Resistant to multidrug; multi-drug resistant; multidrug resistant; Multi-Drug Resistance; Selection Criteria; Basic Amino Acids; Therapeutic; Torulopsis glabrata; Candida glabrata; Nature; Life; programs; Industrial Fungicides; fungicidal; fungicide; Industrial fungicide; Minimum Inhibitory Concentrations; Minimum Inhibitory Concentration measurement; chemical stability; Lytotoxicity; cytotoxicity; Toxicities; Toxic effect; novel; Drug Interactions; Reporting; Property; response; LC/MS; liquid chromatography mass spectrometry; Fungal Drug Resistance; Antifungal Drug Resistance; Antifungal Drug Resistant; Antifungal resistant; Fungus drug resistant; anti-fungal drug resistance; anti-fungal drug resistant; anti-fungal resistance; anti-fungal resistant; antifungal resistance; fungus drug resistance; resistance to anti-fungal; resistance to antifungal; resistant to anti-fungal; resistant to antifungal; Lysis; Cytolysis; Address; Dose; Data; Mammalian Cell; in vivo; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; transmission process; Transmission; Process; Modification; Development; developmental; antimicrobial peptide; anti-microbial peptide; design; designing; Resistance development; Resistant development; developing resistance; Population; Prevalence; Resistance; resistant; mouse model; murine model; combat; alternative treatment; resistant strain; resistance strain; in vitro activity; candidate selection; screening; HepG2; Hep G2; HepG2 cell line; Resistant candida; Hepatitis B Virus; HBV; Homologous Serum Hepatitis Virus; in vivo evaluation; in vivo testing; Candida auris; C auris; C. auris
