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1.
Nat Commun ; 15(1): 5219, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38890312

RESUMO

With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited the ring-stage development of newly invaded merozoites. Here, we select parasites resistant to M-833 and identify mutations in the START lipid transfer protein (PF3D7_0104200, PfSTART1). Introducing PfSTART1 mutations into wildtype parasites reproduces resistance to M-833 as well as to more potent analogues. PfSTART1 binding to the analogues is validated using organic solvent-based Proteome Integral Solubility Alteration (Solvent PISA) assays. Imaging of invading merozoites shows the inhibitors prevent the development of ring-stage parasites potentially by inhibiting the expansion of the encasing parasitophorous vacuole membrane. The PfSTART1-targeting compounds also block transmission to mosquitoes and with multiple stages of the parasite's lifecycle being affected, PfSTART1 represents a drug target with a new mechanism of action.


Assuntos
Acetamidas , Antimaláricos , Plasmodium falciparum , Proteínas de Protozoários , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Plasmodium falciparum/crescimento & desenvolvimento , Acetamidas/farmacologia , Acetamidas/química , Proteínas de Protozoários/metabolismo , Proteínas de Protozoários/genética , Antimaláricos/farmacologia , Antimaláricos/química , Animais , Proteínas de Transporte/metabolismo , Proteínas de Transporte/genética , Mutação , Malária Falciparum/parasitologia , Malária Falciparum/prevenção & controle , Malária Falciparum/tratamento farmacológico , Humanos , Resistência a Medicamentos/genética , Resistência a Medicamentos/efeitos dos fármacos , Estágios do Ciclo de Vida/efeitos dos fármacos
2.
ACS Infect Dis ; 9(9): 1695-1710, 2023 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-37639221

RESUMO

With the resistance increasing to current antimalarial medicines, there is an urgent need to discover new drug targets and to develop new medicines against these targets. We therefore screened the Open Global Health Library of Merck KGaA, Darmstadt, Germany, of 250 compounds against the asexual blood stage of the deadliest malarial parasite Plasmodium falciparum, from which eight inhibitors with low micromolar potency were found. Due to its combined potencies against parasite growth and inhibition of red blood cell invasion, the pyridyl-furan compound OGHL250 was prioritized for further optimization. The potency of the series lead compound (WEHI-518) was improved 250-fold to low nanomolar levels against parasite blood-stage growth. Parasites selected for resistance to a related compound, MMV396797, were also resistant to WEHI-518 as well as KDU731, an inhibitor of the phosphatidylinositol kinase PfPI4KIIIB, suggesting that this kinase is the target of the pyridyl-furan series. Inhibition of PfPI4KIIIB blocks multiple stages of the parasite's life cycle and other potent inhibitors are currently under preclinical development. MMV396797-resistant parasites possess an E1316D mutation in PfPKI4IIIB that clusters with known resistance mutations of other inhibitors of the kinase. Building upon earlier studies that showed that PfPI4KIIIB inhibitors block the development of the invasive merozoite parasite stage, we show that members of the pyridyl-furan series also block invasion and/or the conversion of merozoites into ring-stage intracellular parasites through inhibition of protein secretion and export into red blood cells.


Assuntos
Parasitos , Animais , Plasmodium falciparum/genética , Saúde Global , Eritrócitos , Transporte Proteico , Furanos
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