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Published on: November 22, 2024
Optimized Pyridazinone Nutrient Channel Inhibitors Are Potent and Specific Antimalarial Leads
Michelle M Butler1, Samanthi L Waidyarachchi2, Jinfeng Shao2
1Microbiotix, 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.) mbutler@microbiotix.com.
Researchers developed a new antimalarial drug candidate, MBX-4055, targeting a unique parasite channel to combat drug resistance in *Plasmodium falciparum* malaria.
Area of Science:
- Malariology
- Medicinal Chemistry
- Parasitology
Background:
- Malaria parasites, like *Plasmodium falciparum*, alter host erythrocyte permeability via parasite-associated ion channels for nutrient acquisition.
- Existing antimalarial drug development is hindered by a lack of effective inhibitors targeting these channels.
- Drug resistance in malaria parasites necessitates the urgent discovery of novel therapeutic agents with new mechanisms of action.
Purpose of the Study:
- To develop a potent and specific antimalarial drug lead targeting parasite-induced erythrocyte permeability.
- To optimize drug-like properties, target specificity, and antimalarial activity of pyridazinone derivatives.
- To identify novel antimalarial scaffolds with a defined mechanism of action refractory to acquired resistance.
Main Methods:
- Synthesized 315 derivatives of the pyridazinone MBX-2366 to optimize antimalarial properties.
- Evaluated drug candidates for activity against *Plasmodium falciparum* and specificity against human channels/receptors.
- Utilized single-molecule and single-cell patch-clamp techniques to determine the mechanism of action.
- Assessed in vivo tolerability, pharmacokinetics, and oral absorption of lead compounds.
- Performed extended in vitro selection to evaluate the potential for acquired resistance.
Main Results:
- Generated MBX-4055, a potent derivative active against diverse *Plasmodium falciparum* strains.
- MBX-4055 demonstrated improved oral absorption, favorable pharmacokinetics, and acceptable in vivo tolerability.
- The compound showed no activity against 35 human channels/receptors, indicating high specificity.
- MBX-4055 was refractory to acquired resistance during extended in vitro selection.
- Patch-clamp studies confirmed direct action on the plasmodial surface anion channel.
Conclusions:
- Pyridazinones represent a novel and tractable class of antimalarial scaffolds.
- MBX-4055 targets the plasmodial surface anion channel, a previously unexploited therapeutic target.
- The developed drug candidate exhibits promising drug-like properties and a low propensity for resistance.
- This study provides a new therapeutic strategy against drug-resistant malaria infections.
