title: ELQ-300 prodrugs for enhanced delivery and single-dose cure of malaria.
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.
authors.affiliation: VA Medical Center, Experimental Chemotherapy Laboratory, Portland, Oregon, USA.
authors.forename: Galen P
authors.initials: GP
authors.lastname: Miley
authors.affiliation: VA Medical Center, Experimental Chemotherapy Laboratory, Portland, Oregon, USA.
authors.forename: Sovitj
authors.initials: S
authors.lastname: Pou
authors.affiliation: VA Medical Center, Experimental Chemotherapy Laboratory, Portland, Oregon, USA.
authors.forename: Rolf
authors.initials: R
authors.lastname: Winter
authors.affiliation: VA Medical Center, Experimental Chemotherapy Laboratory, Portland, Oregon, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Nilsen
authors.affiliation: VA Medical Center, Experimental Chemotherapy Laboratory, Portland, Oregon, USA.
authors.forename: Yuexin
authors.initials: Y
authors.lastname: Li
authors.affiliation: VA Medical Center, Experimental Chemotherapy Laboratory, Portland, Oregon, USA.
authors.forename: Jane X
authors.initials: JX
authors.lastname: Kelly
authors.affiliation: Oregon Health & Science University, Department of Molecular Microbiology and Immunology, Portland, Oregon, USA.
authors.forename: Allison M
authors.identifier: http://orcid.org/0000-0002-5006-3611
authors.initials: AM
authors.lastname: Stickles
authors.affiliation: Drexel University College of Medicine, Department of Microbiology and Immunology, Philadelphia, Pennsylvania, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Mather
authors.affiliation: VA Medical Center, Experimental Chemotherapy Laboratory, Portland, Oregon, USA.
authors.forename: Isaac P
authors.initials: IP
authors.lastname: Forquer
authors.affiliation: Drexel University College of Medicine, Department of Microbiology and Immunology, Philadelphia, Pennsylvania, USA.
authors.forename: April M
authors.initials: AM
authors.lastname: Pershing
authors.affiliation: Monash University, Centre for Drug Candidate Optimization, Parkville, Australia.
authors.forename: Karen
authors.initials: K
authors.lastname: White
authors.affiliation: Monash University, Centre for Drug Candidate Optimization, Parkville, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Shackleford
authors.affiliation: Monash University, Centre for Drug Candidate Optimization, Parkville, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Saunders
authors.affiliation: Monash University, Centre for Drug Candidate Optimization, Parkville, Australia.
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
authors.affiliation: Albert Einstein College of Medicine, Departments of Medicine, Pathology, and Microbiology and Immunology, Bronx, New York, USA.
authors.forename: Li-Min
authors.initials: LM
authors.lastname: Ting
authors.affiliation: Albert Einstein College of Medicine, Departments of Medicine, Pathology, and Microbiology and Immunology, Bronx, New York, USA.
authors.forename: Kami
authors.initials: K
authors.lastname: Kim
authors.affiliation: CAMCOR, University of Oregon, Eugene, Oregon, USA.
authors.forename: Lev N
authors.initials: LN
authors.lastname: Zakharov
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Cristina
authors.initials: C
authors.lastname: Donini
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Burrows
authors.affiliation: Drexel University College of Medicine, Department of Microbiology and Immunology, Philadelphia, Pennsylvania, USA Akhil.Vaidya@DrexelMed.edu Susan.Charman@monash.edu riscoem@ohsu.edu.
authors.forename: Akhil B
authors.initials: AB
authors.lastname: Vaidya
authors.affiliation: Monash University, Centre for Drug Candidate Optimization, Parkville, Australia Akhil.Vaidya@DrexelMed.edu Susan.Charman@monash.edu riscoem@ohsu.edu.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.affiliation: VA Medical Center, Experimental Chemotherapy Laboratory, Portland, Oregon, USA Oregon Health & Science University, Department of Molecular Microbiology and Immunology, Portland, Oregon, USA Akhil.Vaidya@DrexelMed.edu Susan.Charman@monash.edu riscoem@ohsu.edu.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Riscoe
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000627:therapeutic use*; D018360:Crystallography, X-Ray; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors; D005260:Female; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects / Q000472:pathogenicity; D011355:Prodrugs / Q000737:chemistry / Q000627:therapeutic use*; D015363:Quinolones / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: C000601913:6-Chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one; D000962:Antimalarials; D011355:Prodrugs; D015363:Quinolones; D014450:Electron Transport Complex III