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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.
Biochem J ; 479(24): 2529-2546, 2022 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-36520108

RESUMO

Transmission blocking interventions can stop malaria parasite transmission from mosquito to human by inhibiting parasite infection in mosquitos. One of the most advanced candidates for a malaria transmission blocking vaccine is Pfs230. Pfs230 is the largest member of the 6-cysteine protein family with 14 consecutive 6-cysteine domains and is expressed on the surface of gametocytes and gametes. Here, we present the crystal structure of the first two 6-cysteine domains of Pfs230. We identified high affinity Pfs230-specific nanobodies that recognized gametocytes and bind to distinct sites on Pfs230, which were isolated from immunized alpacas. Using two non-overlapping Pfs230 nanobodies, we show that these nanobodies significantly blocked P. falciparum transmission and reduced the formation of exflagellation centers. Crystal structures of the transmission blocking nanobodies with the first 6-cysteine domain of Pfs230 confirm that they bind to different epitopes. In addition, these nanobodies bind to Pfs230 in the absence of the prodomain, in contrast with the binding of known Pfs230 transmission blocking antibodies. These results provide additional structural insight into Pfs230 domains and elucidate a mechanism of action of transmission blocking Pfs230 nanobodies.


Assuntos
Malária , Anticorpos de Domínio Único , Animais , Humanos , Plasmodium falciparum/química , Proteínas de Protozoários/química , Antígenos de Protozoários/química , Cisteína , Anticorpos Antiprotozoários
3.
Cell Host Microbe ; 27(4): 642-658.e12, 2020 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-32109369

RESUMO

Artemisin combination therapy (ACT) is the main treatment option for malaria, which is caused by the intracellular parasite Plasmodium. However, increased resistance to ACT highlights the importance of finding new drugs. Recently, the aspartic proteases Plasmepsin IX and X (PMIX and PMX) were identified as promising drug targets. In this study, we describe dual inhibitors of PMIX and PMX, including WM382, that block multiple stages of the Plasmodium life cycle. We demonstrate that PMX is a master modulator of merozoite invasion and direct maturation of proteins required for invasion, parasite development, and egress. Oral administration of WM382 cured mice of P. berghei and prevented blood infection from the liver. In addition, WM382 was efficacious against P. falciparum asexual infection in humanized mice and prevented transmission to mosquitoes. Selection of resistant P. falciparum in vitro was not achievable. Together, these show that dual PMIX and PMX inhibitors are promising candidates for malaria treatment and prevention.


Assuntos
Antimaláricos/farmacologia , Ácido Aspártico Endopeptidases/efeitos dos fármacos , Malária/tratamento farmacológico , Animais , Transmissão de Doença Infecciosa/prevenção & controle , Estágios do Ciclo de Vida/efeitos dos fármacos , Merozoítos/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos
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