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Principal Investigator: Terry Roemer
Organization: PROKARYOTICS, INC.
Fiscal Year: 2024
Award: $295,592
Funding agency: National Institute of Allergy and Infectious Diseases
Widespread azole resistance among Candida and Aspergillus spp. along with emerging echinocandin
resistance in C. glabrata and C. auris raises the specter of untreatable multidrug resistant fungal infections,
even as advances in medicine (cancer chemotherapy, organ transplant, premature infants, HIV/AIDS therapy)
have increased the size of the vulnerable population. Our proposal aims to develop a novel broad spectrum
antifungal therapeutic targeting Glycosylphosphatidylinositol (GPI) biosynthesis to treat life threatening
infections due to drug resistant Candida and Aspergillus with no cross resistance to existing agents. Our
Aims are:
Aim 1 (Phase 1). Demonstrate improved efficacy is achievable by optimizing pharmacokinetic (PK)
properties of the series. Perform metabolic identification (MetID) studies on M743, M720, and the hydrolyzed
core lacking the sidechain to identify oxidative metabolic hotspots to guide a limited Lead Optimization (Lead
Opt) effort to improve PK properties of the series while maintaining potency, spectrum, target selectivity, and
minimizing cytotoxicity. Test up to 2 new analogs in a murine systemic infection model of Candidiasis with and
without 1-aminobenzotriazole (ABT) PK enhancer codosing. Milestone 1. Based on MetID studies, synthesize
up to 30 new M743 analogs. An analog showing an IP-administered dose-dependent > 3 log10 reduction in
fungal burden in a murine Candidiasis model (i.e. superior to M720 efficacy) with or without ABT codosing will
identify the key (and addressable) liability of the series and warrant advancement of the program to Ph 2.
Aim 2 (Phase 2). M743 scale up, Lead Opt and in vitro characterization of compounds. Produce M743
on scale sufficient to supply a full Lead Opt effort based on MetID data and emerging SAR. Characterize
analogs as in Aim 1 with additional emphasis on PK, MOA, reduced serum binding, and cytotoxicity. Milestone
2. Obtain 3g of M743; semisynthesize up to 100 new analogs. Identify up to 3 analogs with acceptable potency
and PK (without ABT codosing), along with validated target engagement, FOR <1 x 109, in vitro synergy with
Gwt1 inhibitor, APX001A (FICI<0.5), progressible activity in serum, and acceptable toxicity (in vivo cytotoxicity
vs. HepG2, in vitro IC50>10 uM vs ion channels, CYPs, critical PANLABS targets) to advance to Aim 3.
Aim 3 (Phase 2). In vivo Characterization. Efficacy of up to 2 compounds will be tested in a murine
Candidiasis (including codosing with APX001 to evaluate in vivo synergy) and Invasive Pulmonary
Aspergillosis infection models without ABT codosing. Milestone 3. Semisynthesize 200 mg of each test
compound. Demonstrate acceptable MIC90 across Candida/Aspergillus spp. Identify suitable formulation for IP
dosing. Conduct dose-ranging studies to gauge exposures and tolerability at higher doses to guide dose
selection. Top analog achieving dose-dependent efficacy in each infection model (> 3 log reduction in burden
over therapeutic duration) and overall favorable drug-like properties will be selected as a preclinical candidate.
Terms: <A fumigatus><A. fumigatus><AIDS therapy><AIDS/HIV><Address><Allergic Bronchopulmonary Aspergillosis><AmB><AmBisome><Amphocil><Amphotec><Amphotercin B><Amphotericin B><Anabolism><Aspergillosis><Aspergillus><Aspergillus fumigatus><Aspergillus resistance><Attenuated><Azole resistance><Azole resistant><Azoles><Binding><Biogenesis><Blood Serum><Bronchopulmonary Aspergillosis><C albicans><C auris><C. albicans><C. auris><C. glabrata><C.albicans><Candida><Candida albicans><Candida auris><Candida glabrata><Candida resistance><Candida resistant isolate><Candidiasis><Candidosis><Cell Body><Cell Wall><Cell surface><Cells><Centers for Disease Control><Centers for Disease Control and Prevention><Centers for Disease Control and Prevention (U.S.)><Chemicals><Chemotherapy Protocol><Chemotherapy Regimen><Chemotherapy-Oncologic Procedure><Clinical><Combination Chemotherapy Regimen><Data><Death Rate><Development><Disseminated candidiasis><Disseminated candidosis><Dose><Drug Interactions><Drug Kinetics><Drug resistance><Drugs><Enhancers><Eukaryota><Eukaryote><Evaluation><Filamentous Fungi><Formulation><Fungal Multidrug Resistance><Fungal Multidrug Resistant><Fungizone><Fungus Diseases><Generalized Growth><Gly-PtdIns><Glycosyl-Phosphatidylinositol><Glycosylated Phosphatidylinositols><Glycosylphosphatidylinositols><Goals><Grafting Procedure><Growth><HIV/AIDS><Hep G2><HepG2><HepG2 cell line><Human><Immune system><In Vitro><Infection><Ion Channel><Ionic Channels><LD-50><LD50><Lead><Lethal Dose 50><Life><Lytotoxicity><Mediating><Medication><Medicine><Membrane Channels><Metabolic><Mice><Mice Mammals><Modeling><Modern Man><Molds><Molecular Interaction><Monilia><Moniliasis><Morbidity><Morbidity - disease rate><Multi-Drug Resistance><Multidrug Resistance><Multiple Anti-fungal Drug Resistance><Multiple Anti-fungal Drug Resistant><Multiple Antifungal Drug Resistance><Multiple Antifungal Drug Resistant><Multiple Drug Resistance><Multiple Drug Resistant><Multiple Fungal Drug Resistance><Murine><Mus><Mycoses><Mysteclin-F><Names><Natural Products><Organ Transplantation><Organ Transplants><Origin of Life><Pathway interactions><Pb element><Pharmaceutical Preparations><Pharmacokinetics><Phase><Phase III study><Phenotype><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Premature Infant><Production><Property><Protein Modification><Proteins><Publishing><Quimioterapia><Reporting><Resistance><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Anti-fungal Drug><Resistance to Multiple Antifungal Drug><Resistance to Multiple Drug><Resistant candida><Resistant to Multiple Anti-fungal Drug><Resistant to Multiple Antifungal Drug><Resistant to Multiple Drug><Resistant to multi-drug><Resistant to multidrug><Sepsis><Series><Serum><Systemic candida><Systemic candida infections><Systemic candidiasis><Systemic infection><Testing><Therapeutic><Therapeutic Fungicides><Therapeutic Index><Tissue Growth><Torulopsis glabrata><Toxic effect><Toxicities><United States Centers for Disease Control><United States Centers for Disease Control and Prevention><Virulence><Vulnerable Populations><World Health Organization><Yeasts><analog><anti-fungal><anti-fungal agents><anti-fungal drug><attenuate><attenuates><biosynthesis><blood infection><bloodstream infection><cancer chemotherapy><candidate selection><clinical development><clinical relevance><clinically relevant><cytotoxicity><developmental><drug resistant><drug/agent><echinocandin resistance><echinocandin resistant><fungal infection><fungal pathogen><fungi pathogen><fungus infection><genome scale><genome-wide><genomewide><health care settings><healthcare settings><heavy metal Pb><heavy metal lead><improved><in vivo><infants born premature><infants born prematurely><inhibitor><innovate><innovation><innovative><lead optimization><mortality><mortality rate><mortality ratio><mouse model><multi-drug resistant><multidrug resistant><murine model><name><named><naming><naturally occurring product><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><ontogeny><organ allograft><organ graft><organ xenograft><pathogen><pathogenic fungus><pathway><phase 3 study><pre-clinical><preclinical><premature baby><premature infant human><preterm baby><preterm infant><preterm infant human><priority pathogen><programs><pulmonary aspergillosis><resistance among Candida><resistance in Aspergillus><resistance in Candida><resistance to Drug><resistance to azole><resistant><resistant Aspergillus><resistant Candida strains><resistant to Drug><resistant to azole><scale up><screening><screenings><standard of care><synergism><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><vulnerable group><vulnerable individual><vulnerable people>