ELQ-300 prodrugs for enhanced delivery and single-dose cure of malaria

Galen P Miley, Sovitj Pou, Rolf Winter, Aaron Nilsen, Yuexin Li, Jane X Kelly, Allison M Stickles, Michael W Mather, Isaac P Forquer, April M Pershing, Karen White, David Shackleford, Jessica Saunders, Gong Chen, Li-Min Ting, Kami Kim, Lev N Zakharov, Cristina Donini, Jeremy N Burrows, Akhil B Valdya & 2 others Susan A Charman, Michael K Riscoe

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)5555-5560
Number of pages6
JournalAntimicrobial Agents and Chemotherapy
Volume59
Issue number9
DOIs
Publication statusPublished - 2015

Cite this

Miley, G. P., Pou, S., Winter, R., Nilsen, A., Li, Y., Kelly, J. X., ... Riscoe, M. K. (2015). ELQ-300 prodrugs for enhanced delivery and single-dose cure of malaria. Antimicrobial Agents and Chemotherapy, 59(9), 5555-5560. https://doi.org/10.1128/AAC.01183-15
Miley, Galen P ; Pou, Sovitj ; Winter, Rolf ; Nilsen, Aaron ; Li, Yuexin ; Kelly, Jane X ; Stickles, Allison M ; Mather, Michael W ; Forquer, Isaac P ; Pershing, April M ; White, Karen ; Shackleford, David ; Saunders, Jessica ; Chen, Gong ; Ting, Li-Min ; Kim, Kami ; Zakharov, Lev N ; Donini, Cristina ; Burrows, Jeremy N ; Valdya, Akhil B ; Charman, Susan A ; Riscoe, Michael K. / ELQ-300 prodrugs for enhanced delivery and single-dose cure of malaria. In: Antimicrobial Agents and Chemotherapy. 2015 ; Vol. 59, No. 9. pp. 5555-5560.
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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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Miley, GP, Pou, S, Winter, R, Nilsen, A, Li, Y, Kelly, JX, Stickles, AM, Mather, MW, Forquer, IP, Pershing, AM, White, K, Shackleford, D, Saunders, J, Chen, G, Ting, L-M, Kim, K, Zakharov, LN, Donini, C, Burrows, JN, Valdya, AB, Charman, SA & Riscoe, MK 2015, 'ELQ-300 prodrugs for enhanced delivery and single-dose cure of malaria' Antimicrobial Agents and Chemotherapy, vol. 59, no. 9, pp. 5555-5560. https://doi.org/10.1128/AAC.01183-15

ELQ-300 prodrugs for enhanced delivery and single-dose cure of malaria. / Miley, Galen P; Pou, Sovitj; Winter, Rolf; Nilsen, Aaron; Li, Yuexin; Kelly, Jane X; Stickles, Allison M; Mather, Michael W; Forquer, Isaac P; Pershing, April M; White, Karen; Shackleford, David; Saunders, Jessica; Chen, Gong; Ting, Li-Min; Kim, Kami; Zakharov, Lev N; Donini, Cristina; Burrows, Jeremy N; Valdya, Akhil B; Charman, Susan A; Riscoe, Michael K.

In: Antimicrobial Agents and Chemotherapy, Vol. 59, No. 9, 2015, p. 5555-5560.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - ELQ-300 prodrugs for enhanced delivery and single-dose cure of malaria

AU - Miley, Galen P

AU - Pou, Sovitj

AU - Winter, Rolf

AU - Nilsen, Aaron

AU - Li, Yuexin

AU - Kelly, Jane X

AU - Stickles, Allison M

AU - Mather, Michael W

AU - Forquer, Isaac P

AU - Pershing, April M

AU - White, Karen

AU - Shackleford, David

AU - Saunders, Jessica

AU - Chen, Gong

AU - Ting, Li-Min

AU - Kim, Kami

AU - Zakharov, Lev N

AU - Donini, Cristina

AU - Burrows, Jeremy N

AU - Valdya, Akhil B

AU - Charman, Susan A

AU - Riscoe, Michael K

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

UR - http://aac.asm.org.ezproxy.lib.monash.edu.au/content/59/9/5555.full.pdf+html

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DO - 10.1128/AAC.01183-15

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JF - Antimicrobial Agents and Chemotherapy

SN - 1098-6596

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