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Research ArticleArticle

Optimized Pyridazinone Nutrient Channel Inhibitors Are Potent and Specific Antimalarial Leads

Michelle M. Butler, Samanthi L. Waidyarachchi, Jinfeng Shao, Son T. Nguyen, Xiaoyuan Ding, Steven C. Cardinale, Lucas R. Morin, Steven M. Kwasny, Mai Ito, Jeanine Gezelle, María B. Jiménez-Díaz, Iñigo Angulo-Barturen, Robert T. Jacobs, Jeremy N. Burrows, Zachary D. Aron, Terry L. Bowlin and Sanjay A. Desai
Molecular Pharmacology September 2022, 102 (3) 172-182; DOI: https://doi.org/10.1124/molpharm.122.000549
Michelle M. Butler
Microbiotix, Inc., One Innovation Dr., Worcester, Massachusetts (M.M.B., S.L.W., S.T.N., X.D., S.C.C., L.R.M., S.M.K., Z.D.A., T.L.B.); Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland (J.S., M.I., J.G., S.A.D.); The Art of Discovery, SL, Biscay, Basque Country, Spain (M.B.J.-D., I.A.-B.); and Medicines for Malaria Venture, Geneva, Switzerland (R.T.J., J.N.B.)
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Samanthi L. Waidyarachchi
Microbiotix, Inc., One Innovation Dr., Worcester, Massachusetts (M.M.B., S.L.W., S.T.N., X.D., S.C.C., L.R.M., S.M.K., Z.D.A., T.L.B.); Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland (J.S., M.I., J.G., S.A.D.); The Art of Discovery, SL, Biscay, Basque Country, Spain (M.B.J.-D., I.A.-B.); and Medicines for Malaria Venture, Geneva, Switzerland (R.T.J., J.N.B.)
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Jinfeng Shao
Microbiotix, Inc., One Innovation Dr., Worcester, Massachusetts (M.M.B., S.L.W., S.T.N., X.D., S.C.C., L.R.M., S.M.K., Z.D.A., T.L.B.); Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland (J.S., M.I., J.G., S.A.D.); The Art of Discovery, SL, Biscay, Basque Country, Spain (M.B.J.-D., I.A.-B.); and Medicines for Malaria Venture, Geneva, Switzerland (R.T.J., J.N.B.)
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Son T. Nguyen
Microbiotix, Inc., One Innovation Dr., Worcester, Massachusetts (M.M.B., S.L.W., S.T.N., X.D., S.C.C., L.R.M., S.M.K., Z.D.A., T.L.B.); Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland (J.S., M.I., J.G., S.A.D.); The Art of Discovery, SL, Biscay, Basque Country, Spain (M.B.J.-D., I.A.-B.); and Medicines for Malaria Venture, Geneva, Switzerland (R.T.J., J.N.B.)
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Xiaoyuan Ding
Microbiotix, Inc., One Innovation Dr., Worcester, Massachusetts (M.M.B., S.L.W., S.T.N., X.D., S.C.C., L.R.M., S.M.K., Z.D.A., T.L.B.); Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland (J.S., M.I., J.G., S.A.D.); The Art of Discovery, SL, Biscay, Basque Country, Spain (M.B.J.-D., I.A.-B.); and Medicines for Malaria Venture, Geneva, Switzerland (R.T.J., J.N.B.)
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Steven C. Cardinale
Microbiotix, Inc., One Innovation Dr., Worcester, Massachusetts (M.M.B., S.L.W., S.T.N., X.D., S.C.C., L.R.M., S.M.K., Z.D.A., T.L.B.); Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland (J.S., M.I., J.G., S.A.D.); The Art of Discovery, SL, Biscay, Basque Country, Spain (M.B.J.-D., I.A.-B.); and Medicines for Malaria Venture, Geneva, Switzerland (R.T.J., J.N.B.)
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Lucas R. Morin
Microbiotix, Inc., One Innovation Dr., Worcester, Massachusetts (M.M.B., S.L.W., S.T.N., X.D., S.C.C., L.R.M., S.M.K., Z.D.A., T.L.B.); Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland (J.S., M.I., J.G., S.A.D.); The Art of Discovery, SL, Biscay, Basque Country, Spain (M.B.J.-D., I.A.-B.); and Medicines for Malaria Venture, Geneva, Switzerland (R.T.J., J.N.B.)
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Steven M. Kwasny
Microbiotix, Inc., One Innovation Dr., Worcester, Massachusetts (M.M.B., S.L.W., S.T.N., X.D., S.C.C., L.R.M., S.M.K., Z.D.A., T.L.B.); Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland (J.S., M.I., J.G., S.A.D.); The Art of Discovery, SL, Biscay, Basque Country, Spain (M.B.J.-D., I.A.-B.); and Medicines for Malaria Venture, Geneva, Switzerland (R.T.J., J.N.B.)
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Mai Ito
Microbiotix, Inc., One Innovation Dr., Worcester, Massachusetts (M.M.B., S.L.W., S.T.N., X.D., S.C.C., L.R.M., S.M.K., Z.D.A., T.L.B.); Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland (J.S., M.I., J.G., S.A.D.); The Art of Discovery, SL, Biscay, Basque Country, Spain (M.B.J.-D., I.A.-B.); and Medicines for Malaria Venture, Geneva, Switzerland (R.T.J., J.N.B.)
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Jeanine Gezelle
Microbiotix, Inc., One Innovation Dr., Worcester, Massachusetts (M.M.B., S.L.W., S.T.N., X.D., S.C.C., L.R.M., S.M.K., Z.D.A., T.L.B.); Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland (J.S., M.I., J.G., S.A.D.); The Art of Discovery, SL, Biscay, Basque Country, Spain (M.B.J.-D., I.A.-B.); and Medicines for Malaria Venture, Geneva, Switzerland (R.T.J., J.N.B.)
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María B. Jiménez-Díaz
Microbiotix, Inc., One Innovation Dr., Worcester, Massachusetts (M.M.B., S.L.W., S.T.N., X.D., S.C.C., L.R.M., S.M.K., Z.D.A., T.L.B.); Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland (J.S., M.I., J.G., S.A.D.); The Art of Discovery, SL, Biscay, Basque Country, Spain (M.B.J.-D., I.A.-B.); and Medicines for Malaria Venture, Geneva, Switzerland (R.T.J., J.N.B.)
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Iñigo Angulo-Barturen
Microbiotix, Inc., One Innovation Dr., Worcester, Massachusetts (M.M.B., S.L.W., S.T.N., X.D., S.C.C., L.R.M., S.M.K., Z.D.A., T.L.B.); Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland (J.S., M.I., J.G., S.A.D.); The Art of Discovery, SL, Biscay, Basque Country, Spain (M.B.J.-D., I.A.-B.); and Medicines for Malaria Venture, Geneva, Switzerland (R.T.J., J.N.B.)
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Robert T. Jacobs
Microbiotix, Inc., One Innovation Dr., Worcester, Massachusetts (M.M.B., S.L.W., S.T.N., X.D., S.C.C., L.R.M., S.M.K., Z.D.A., T.L.B.); Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland (J.S., M.I., J.G., S.A.D.); The Art of Discovery, SL, Biscay, Basque Country, Spain (M.B.J.-D., I.A.-B.); and Medicines for Malaria Venture, Geneva, Switzerland (R.T.J., J.N.B.)
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Jeremy N. Burrows
Microbiotix, Inc., One Innovation Dr., Worcester, Massachusetts (M.M.B., S.L.W., S.T.N., X.D., S.C.C., L.R.M., S.M.K., Z.D.A., T.L.B.); Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland (J.S., M.I., J.G., S.A.D.); The Art of Discovery, SL, Biscay, Basque Country, Spain (M.B.J.-D., I.A.-B.); and Medicines for Malaria Venture, Geneva, Switzerland (R.T.J., J.N.B.)
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Zachary D. Aron
Microbiotix, Inc., One Innovation Dr., Worcester, Massachusetts (M.M.B., S.L.W., S.T.N., X.D., S.C.C., L.R.M., S.M.K., Z.D.A., T.L.B.); Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland (J.S., M.I., J.G., S.A.D.); The Art of Discovery, SL, Biscay, Basque Country, Spain (M.B.J.-D., I.A.-B.); and Medicines for Malaria Venture, Geneva, Switzerland (R.T.J., J.N.B.)
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Terry L. Bowlin
Microbiotix, Inc., One Innovation Dr., Worcester, Massachusetts (M.M.B., S.L.W., S.T.N., X.D., S.C.C., L.R.M., S.M.K., Z.D.A., T.L.B.); Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland (J.S., M.I., J.G., S.A.D.); The Art of Discovery, SL, Biscay, Basque Country, Spain (M.B.J.-D., I.A.-B.); and Medicines for Malaria Venture, Geneva, Switzerland (R.T.J., J.N.B.)
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Sanjay A. Desai
Microbiotix, Inc., One Innovation Dr., Worcester, Massachusetts (M.M.B., S.L.W., S.T.N., X.D., S.C.C., L.R.M., S.M.K., Z.D.A., T.L.B.); Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland (J.S., M.I., J.G., S.A.D.); The Art of Discovery, SL, Biscay, Basque Country, Spain (M.B.J.-D., I.A.-B.); and Medicines for Malaria Venture, Geneva, Switzerland (R.T.J., J.N.B.)
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Abstract

Human and animal malaria parasites increase their host erythrocyte permeability to a broad range of solutes as mediated by parasite-associated ion channels. Molecular and pharmacological studies have implicated an essential role in parasite nutrient acquisition, but inhibitors suitable for development of antimalarial drugs are missing. Here, we generated a potent and specific drug lead using Plasmodium falciparum, a virulent human pathogen, and derivatives of MBX-2366, a nanomolar affinity pyridazinone inhibitor from a high-throughput screen. As this screening hit lacks the bioavailability and stability needed for in vivo efficacy, we synthesized 315 derivatives to optimize drug-like properties, establish target specificity, and retain potent activity against the parasite-induced permeability. Using a robust, iterative pipeline, we generated MBX-4055, a derivative active against divergent human parasite strains. MBX-4055 has improved oral absorption with acceptable in vivo tolerability and pharmacokinetics. It also has no activity against a battery of 35 human channels and receptors and is refractory to acquired resistance during extended in vitro selection. Single-molecule and single-cell patch-clamp indicate direct action on the plasmodial surface anion channel, a channel linked to parasite-encoded RhopH proteins. These studies identify pyridazinones as novel and tractable antimalarial scaffolds with a defined mechanism of action.

SIGNIFICANCE STATEMENT Because antimalarial drugs are prone to evolving resistance in the virulent human P. falciparum pathogen, new therapies are needed. This study has now developed a novel drug-like series of pyridazinones that target an unexploited parasite anion channel on the host cell surface, display excellent in vitro and in vivo ADME properties, are refractory to acquired resistance, and demonstrate a well defined mechanism of action.

Footnotes

    • Received April 26, 2022.
    • Accepted June 29, 2022.
  • This work was supported by National Institutes of Health National Institute of Allergy and Infectious Diseases [Grant R43-AI100339 (Phase (M.M.B.) I)] and [Grant R44-AI100339 (Phases (M.M.B.) II and IIB)]; the Intramural Research Program of National Institutes of Health National Institute of Allergy and Infectious Diseases; (S.A.D.) and the Medicines for Malaria Venture (S.A.D.).

  • No author has an actual or perceived conflict of interest with the contents of this article.

  • https://doi.org/10.1124/molpharm.122.000549.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • U.S. Government work not protected by U.S. copyright.
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Molecular Pharmacology: 102 (3)
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Research ArticleArticle

Pyridazinone Antimalarial Leads

Michelle M. Butler, Samanthi L. Waidyarachchi, Jinfeng Shao, Son T. Nguyen, Xiaoyuan Ding, Steven C. Cardinale, Lucas R. Morin, Steven M. Kwasny, Mai Ito, Jeanine Gezelle, María B. Jiménez-Díaz, Iñigo Angulo-Barturen, Robert T. Jacobs, Jeremy N. Burrows, Zachary D. Aron, Terry L. Bowlin and Sanjay A. Desai
Molecular Pharmacology September 1, 2022, 102 (3) 172-182; DOI: https://doi.org/10.1124/molpharm.122.000549

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Research ArticleArticle

Pyridazinone Antimalarial Leads

Michelle M. Butler, Samanthi L. Waidyarachchi, Jinfeng Shao, Son T. Nguyen, Xiaoyuan Ding, Steven C. Cardinale, Lucas R. Morin, Steven M. Kwasny, Mai Ito, Jeanine Gezelle, María B. Jiménez-Díaz, Iñigo Angulo-Barturen, Robert T. Jacobs, Jeremy N. Burrows, Zachary D. Aron, Terry L. Bowlin and Sanjay A. Desai
Molecular Pharmacology September 1, 2022, 102 (3) 172-182; DOI: https://doi.org/10.1124/molpharm.122.000549
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