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Journal article
ELQ-300 Prodrugs for Enhanced Delivery and Single-Dose Cure of Malaria
Antimicrobial agents and chemotherapy, v 59(9), pp 5555-5560
14 Aug 2015
PMID: 26124159
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
ELQ-300 is a preclinical candidate that targets the liver and blood stages of Plasmodium falciparum, as well as the forms that are crucial to transmission of disease: gametocytes, zygotes, and ookinetes. A significant obstacle to the clinical development of ELQ-300 is related to its physicochemical properties. Its relatively poor aqueous solubility and high crystallinity limit absorption to the degree that only low blood concentrations can be achieved following oral dosing. While these low blood concentrations are sufficient for therapy, the levels are too low to establish an acceptable safety margin required by regulatory agencies for clinical development. One way to address the challenging physicochemical properties of ELQ-300 is through the development of prodrugs. Here, we profile ELQ-337, a bioreversible O-linked carbonate ester prodrug of the parent molecule. At the molar equivalent dose of 3 mg/kg of body weight, the delivery of ELQ-300 from ELQ-337 is enhanced by 3- to 4-fold, reaching a maximum concentration of drug in serum (Cmax) of 5.9 μM by 6 h after oral administration, and unlike ELQ-300 at any dose, ELQ-337 provides single-dose cures of patent malaria infections in mice at low-single-digit milligram per kilogram doses. Our findings show that the prodrug strategy represents a viable approach to overcome the physicochemical limitations of ELQ-300 to deliver the active drug to the bloodstream at concentrations sufficient for safety and toxicology studies, as well as achieving single-dose cures.
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Details
- Title
- ELQ-300 Prodrugs for Enhanced Delivery and Single-Dose Cure of Malaria
- Creators
- Galen P Miley - Portland VA Medical CenterSovitj Pou - Portland VA Medical CenterRolf Winter - Portland VA Medical CenterAaron Nilsen - Portland VA Medical CenterYuexin Li - Portland VA Medical CenterJane X Kelly - Portland VA Medical CenterAllison M Stickles - Oregon Health & Science UniversityMichael W Mather - Drexel UniversityIsaac P Forquer - Portland VA Medical CenterApril M Pershing - Drexel UniversityKaren White - Monash University, Parkville campusDavid Shackleford - Monash University, Parkville campusJessica Saunders - Monash University, Parkville campusGong Chen - Monash University, Parkville campusLi-Min Ting - Albert Einstein College of MedicineKami Kim - Albert Einstein College of MedicineLev N Zakharov - University of OregonCristina Donini - Medicines for Malaria VentureJeremy N Burrows - Medicines for Malaria VentureAkhil B Vaidya - Drexel UniversitySusan A Charman - Monash University, Parkville campusMichael K Riscoe - Portland VA Medical Center
- Publication Details
- Antimicrobial agents and chemotherapy, v 59(9), pp 5555-5560
- Publisher
- American Society for Microbiology
- Number of pages
- 6
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000364343900058
- Scopus ID
- 2-s2.0-84940937886
- Other Identifier
- 991019168354304721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Microbiology
- Pharmacology & Pharmacy