In Vitro and in Vivo Activity of Multitarget Inhibitors against Trypanosoma brucei

Gyongseon Yang; Wei Zhu; Yang Wang; Guozhong Huang; Soo Young Byun; Gahee Choi; Kai Li; Zhuoli Huang; Roberto Docampo; Eric Oldfield; Joo Hwan No

doi:10.1021/acsinfecdis.5b00068

In Vitro and in Vivo Activity of Multitarget Inhibitors against Trypanosoma brucei

Gyongseon Yang, Wei Zhu, Yang Wang, Guozhong Huang, Soo Young Byun, Gahee Choi, Kai Li, Zhuoli Huang, Roberto Docampo, Eric Oldfield, Joo Hwan No

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

We tested a series of amidine and related compounds against Trypanosoma brucei. The most active compound was a biphenyldiamidine that had an EC₅₀ of 7.7 nM against bloodstream-form parasites. There was little toxicity against two human cell lines with CC₅₀ > 100 μM. There was also good in vivo activity in a mouse model of infection with 100% survival at 3 mg/kg i.p. The most potent lead blocked replication of kinetoplast DNA (k-DNA), but not nuclear DNA, in the parasite. Some compounds also inhibited the enzyme farnesyl diphosphate synthase (FPPS), and some were uncouplers of oxidative phosphorylation. We developed a computational model for T. brucei cell growth inhibition (R² = 0.76) using DNA ΔT_m values for inhibitor binding combined with T. brucei FPPS IC₅₀ values. Overall, the results suggest that it may be possible to develop multitarget drug leads against T. brucei that act by inhibiting both k-DNA replication and isoprenoid biosynthesis.

Original language	English (US)
Pages (from-to)	388-398
Number of pages	11
Journal	ACS Infectious Diseases
Volume	1
Issue number	8
DOIs	https://doi.org/10.1021/acsinfecdis.5b00068
State	Published - Jan 8 2016

Keywords

computational modeling
farnesyl diphosphate synthase
kinetoplast DNA
proton motive force
sleeping sickness

ASJC Scopus subject areas

Infectious Diseases

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10.1021/acsinfecdis.5b00068

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title = "In Vitro and in Vivo Activity of Multitarget Inhibitors against Trypanosoma brucei",

abstract = "We tested a series of amidine and related compounds against Trypanosoma brucei. The most active compound was a biphenyldiamidine that had an EC50 of 7.7 nM against bloodstream-form parasites. There was little toxicity against two human cell lines with CC50 > 100 μM. There was also good in vivo activity in a mouse model of infection with 100% survival at 3 mg/kg i.p. The most potent lead blocked replication of kinetoplast DNA (k-DNA), but not nuclear DNA, in the parasite. Some compounds also inhibited the enzyme farnesyl diphosphate synthase (FPPS), and some were uncouplers of oxidative phosphorylation. We developed a computational model for T. brucei cell growth inhibition (R2 = 0.76) using DNA ΔTm values for inhibitor binding combined with T. brucei FPPS IC50 values. Overall, the results suggest that it may be possible to develop multitarget drug leads against T. brucei that act by inhibiting both k-DNA replication and isoprenoid biosynthesis.",

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author = "Gyongseon Yang and Wei Zhu and Yang Wang and Guozhong Huang and Byun, {Soo Young} and Gahee Choi and Kai Li and Zhuoli Huang and Roberto Docampo and Eric Oldfield and No, {Joo Hwan}",

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AU - Yang, Gyongseon

AU - Zhu, Wei

AU - Wang, Yang

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AU - Byun, Soo Young

AU - Choi, Gahee

AU - Li, Kai

AU - Huang, Zhuoli

AU - Docampo, Roberto

AU - Oldfield, Eric

AU - No, Joo Hwan

PY - 2016/1/8

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N2 - We tested a series of amidine and related compounds against Trypanosoma brucei. The most active compound was a biphenyldiamidine that had an EC50 of 7.7 nM against bloodstream-form parasites. There was little toxicity against two human cell lines with CC50 > 100 μM. There was also good in vivo activity in a mouse model of infection with 100% survival at 3 mg/kg i.p. The most potent lead blocked replication of kinetoplast DNA (k-DNA), but not nuclear DNA, in the parasite. Some compounds also inhibited the enzyme farnesyl diphosphate synthase (FPPS), and some were uncouplers of oxidative phosphorylation. We developed a computational model for T. brucei cell growth inhibition (R2 = 0.76) using DNA ΔTm values for inhibitor binding combined with T. brucei FPPS IC50 values. Overall, the results suggest that it may be possible to develop multitarget drug leads against T. brucei that act by inhibiting both k-DNA replication and isoprenoid biosynthesis.

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In Vitro and in Vivo Activity of Multitarget Inhibitors against Trypanosoma brucei

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