Design, Synthesis, and Optimization of Macrocyclic Peptides as Species-Selective Antimalaria Proteasome Inhibitors

Zhang, Hao; Ginn, John D.; Wen-hu, Zhan; Liu, Yi J.; Leung, Annie; Toita, Akinori; Okamoto, Rei; Wong, Tzu‐Tshin; Imaeda, Toshihiro; Hara, Ryujiro; Yukawa, Takafumi; Michino, Mayako; Vendôme, Jérémie; Beuming, Thijs; Sato, Kenjiro; Aso, Kazuyoshi; Meinke, Peter T.; Nathan, Carl; Kirkman, Laura A.; Lin, Gang

doi:10.1021/acs.jmedchem.2c00611

Cited by 16 publications

(29 citation statements)

References 43 publications

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“…IC 50 values of all compounds against Pf20S β5, human c-20S β5c, and i-20S β5i were determined in 96-well plates as reported. 22 Antimalarial Activity in the Erythrocytic Stage. Parasite growth inhibition assays were performed as reported.…”

Section: (5s8s11s)-8-((13-dioxan-2-yl)methyl)-11-(11-dioxidoisothiazo...mentioning

confidence: 99%

“…All PAMPA assays were performed as reported. 22 Propranolol was used as a positive control compound. Methyclothiazide was used as a negative control compound.…”

Section: (5s8s11s)-8-((13-dioxan-2-yl)methyl)-11-(11-dioxidoisothiazo...mentioning

confidence: 99%

“…All the MDR1 assays were performed as reported. 22 Lucifer Yellow was co-incubated with the test compound as a membrane integrity marker. Digoxin was used as a positive control compound.…”

Section: (5s8s11s)-8-((13-dioxan-2-yl)methyl)-11-(11-dioxidoisothiazo...mentioning

confidence: 99%

“…The kinetic solubility of the compounds was determined as reported. 22 Diazepam was included as the positive control in each experiment.…”

Section: (5s8s11s)-8-((13-dioxan-2-yl)methyl)-11-(11-dioxidoisothiazo...mentioning

confidence: 99%

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Structure–Activity Relationship Studies of Antimalarial Plasmodium Proteasome Inhibitors─Part II

et al. 2023

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With increasing reports of resistance to artemisinins and artemisinin-combination therapies, targeting the Plasmodium proteasome is a promising strategy for antimalarial development.We recently reported a highly selective Plasmodium falciparum proteasome inhibitor with anti-malarial activity in the humanized mouse model. To balance the permeability of the series of macrocycles with other drug-like properties, we conducted further structure−activity relationship studies on a biphenyl ether-tethered macrocyclic scaffold. Extensive SAR studies around the P1, P3, and P5 groups and peptide backbone identified compound TDI-8414. TDI-8414 showed nanomolar antiparasitic activity, no toxicity to HepG2 cells, high selectivity against the Plasmodium proteasome over the human constitutive proteasome and immunoproteasome, improved solubility and PAMPA permeability, and enhanced metabolic stability in microsomes and plasma of both humans and mice.

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Section: (5s8s11s)-8-((13-dioxan-2-yl)methyl)-11-(11-dioxidoisothiazo...mentioning

confidence: 99%

“…All PAMPA assays were performed as reported. 22 Propranolol was used as a positive control compound. Methyclothiazide was used as a negative control compound.…”

Section: (5s8s11s)-8-((13-dioxan-2-yl)methyl)-11-(11-dioxidoisothiazo...mentioning

confidence: 99%

“…All the MDR1 assays were performed as reported. 22 Lucifer Yellow was co-incubated with the test compound as a membrane integrity marker. Digoxin was used as a positive control compound.…”

Section: (5s8s11s)-8-((13-dioxan-2-yl)methyl)-11-(11-dioxidoisothiazo...mentioning

confidence: 99%

“…The kinetic solubility of the compounds was determined as reported. 22 Diazepam was included as the positive control in each experiment.…”

Section: (5s8s11s)-8-((13-dioxan-2-yl)methyl)-11-(11-dioxidoisothiazo...mentioning

confidence: 99%

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Structure–Activity Relationship Studies of Antimalarial Plasmodium Proteasome Inhibitors─Part II

et al. 2023

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“…Most importantly, proteasome inhibitors strongly synergize artemisinin-mediated killing of Plasmodium in vitro and in vivo. 17…”

Section: Introductionmentioning

confidence: 99%

Development of Highly Selective Epoxyketone-based Plasmodium Proteasome Inhibitors with Negligible Cytotoxicity

Almaliti

Fajtová

Calla

et al. 2022

Preprint

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Here we present remarkable epoxyketone-based proteasome inhibitors with low nanomolar in vitro potency for blood-stage Plasmodium falciparum and low cytotoxicity for human cells. Our best compound has more than 2,600-fold greater selectivity for erythrocytic-stage P. falciparum over HepG2 cells, which is largely driven by the accommodation of the parasite proteasome for a D-amino acid in the P3 position and the preference for a difluorobenzyl group in the P1 position. These compounds also significantly reduce parasitemia in a P. berghei mouse infection model and prolong survival of animals by an average of 6 days. The current epoxyketone inhibitors are ideal starting compounds for orally bioavailable anti-malarial drugs.

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Development of Potent and Highly Selective Epoxyketone‐Based Plasmodium Proteasome Inhibitors

Almaliti

Fajtová

Calla

et al. 2023

Chemistry A European J

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Here we present remarkable epoxyketone-based proteasome inhibitors with low nanomolar in vitro potency for bloodstage Plasmodium falciparum and low cytotoxicity for human cells. Our best compound has more than 2,000-fold greater selectivity for erythrocytic-stage P. falciparum over HepG2 and H460 cells, which is largely driven by the accommodation of the parasite proteasome for a D-amino acid in the P3 position and the preference for a difluorobenzyl group in the P1 position. We isolated the proteasome from P. falciparum cell extracts and determined that the best compound is 171-fold more potent at inhibiting the β5 subunit of P. falciparum proteasome when compared to the same subunit of the human constitutive proteasome. These compounds also significantly reduce parasitemia in a P. berghei mouse infection model and prolong survival of animals by an average of 6 days. The current epoxyketone inhibitors are ideal starting compounds for orally bioavailable antimalarial drugs.

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Design, Synthesis, and Optimization of Macrocyclic Peptides as Species-Selective Antimalaria Proteasome Inhibitors

Cited by 16 publications

References 43 publications

Structure–Activity Relationship Studies of Antimalarial Plasmodium Proteasome Inhibitors─Part II

Structure–Activity Relationship Studies of Antimalarial Plasmodium Proteasome Inhibitors─Part II

Development of Highly Selective Epoxyketone-based Plasmodium Proteasome Inhibitors with Negligible Cytotoxicity

Development of Potent and Highly Selective Epoxyketone‐Based Plasmodium Proteasome Inhibitors

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