Galen P. Miley1, Sovitj Pou1, R.F. Winter1, Aaron Nilsen1, Yuexin Li1, Jane X. Kelly1, Allison M. Stickles2, Michael W. Mather3, Isaac Forquer1, April M. Pershing3, Karen L. White4, David M. Shackleford4, Jessica Saunders4, Gong Chen4, Li-Min Ting5, Kami Kim5, Lev N. Zakharov6, Cristina Donini7, Jeremy N. Burrows7, Akhil B. Vaidya3, Susan A. Charman4, Michael K. Riscoe2,1
1VA Medical Center, Experimental Chemotherapy Laboratory, Portland, Oregon, USA
2Oregon Health & Science University, Department of Molecular Microbiology and Immunology, Portland, Oregon, USA
3Drexel University College of Medicine, Department of Microbiology and Immunology, Philadelphia, Pennsylvania, USA
4Monash University, Centre for Drug Candidate Optimization, Parkville, Australia
5Albert Einstein College of Medicine, Departments of Medicine, Pathology, and Microbiology and Immunology, Bronx, New York, USA
6CAMCOR, University of Oregon, Eugene, Oregon, USA
7Medicines for Malaria Venture, Geneva, Switzerland
Tóm tắt
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 (
C
max
) 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.
