PF-429242, a Subtilisin Inhibitor, Is Effective in vitro Against Leishmania infantum

Machado, Patrícia de Almeida; Gomes, Pollyanna Stephanie; Midlej, Victor; Coimbra, Elaine Soares; Guedes, Herbert Leonel de Matos

doi:10.3389/fmicb.2021.583834

Cited by 26 publications

(20 citation statements)

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“…TPCK has already been shown to reduce serine protease activity of L. amazonensis [ 34 ]. Interestingly, PF-429242, a serine protease inhibitor previously studied by our group, was active against both L. infantum promastigotes (IC 50 = 2.78 μM) and amastigotes (IC 50 = 14.07 μM), displaying parasite selectivity over the host cell [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

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Effects of a Serine Protease Inhibitor N-p-Tosyl-L-phenylalanine Chloromethyl Ketone (TPCK) on Leishmania amazonensis and Leishmania infantum

et al. 2022

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Studies have previously demonstrated the importance of serine proteases in Leishmania. A well-known serine protease inhibitor, TPCK, was used in the present study to evaluate its in vitro and in vivo antileishmanial effects and determine its mechanism of action. Despite slight toxicity against mammalian cells (CC50 = 138.8 µM), TPCK was selective for the parasite due to significant activity against L. amazonensis and L. infantum promastigote forms (IC50 = 14.6 and 31.7 µM for L. amazonensis PH8 and Josefa strains, respectively, and 11.3 µM for L. infantum) and intracellular amastigotes (IC50 values = 14.2 and 16.6 µM for PH8 and Josefa strains, respectively, and 21.7 µM for L. infantum). Leishmania parasites treated with TPCK presented mitochondrial alterations, oxidative stress, modifications in lipid content, flagellar alterations, and cytoplasmic vacuoles, all of which are factors that could be considered as contributing to the death of the parasites. Furthermore, BALB/c mice infected with L. amazonensis and treated with TPCK had a reduction in lesion size and parasite loads in the footpad and spleen. In BALB/c mice infected with L. infantum, TPCK also caused a reduction in the parasite loads in the liver and spleen. Therefore, we highlight the antileishmanial effect of the assessed serine protease inhibitor, proposing a potential therapeutic target in Leishmania as well as a possible new alternative treatment for leishmaniasis.

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Section: Discussionmentioning

confidence: 99%

“…In this work, TPCK showed low toxicity in mammalian cells and was found to be selective for the parasite when compared to host cells. Interestingly, our research group has previously demonstrated that PF-429242 also exhibits low toxicity against peritoneal macrophages [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of a Serine Protease Inhibitor N-p-Tosyl-L-phenylalanine Chloromethyl Ketone (TPCK) on Leishmania amazonensis and Leishmania infantum

et al. 2022

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“…48 The increased level of ROS was observed in L. infantum promastigotes after treatment with PF-429242 (a subtilisin inhibitor) in contrast to untreated control parasites. 49 Also, caffeic acid induces high ROS generation through oxidative burst, which leads to the death of Leishmania amazonensis promastigotes. 50 The health of any cell depends on its intact boundary or cellular membrane.…”

Section: Discussionmentioning

confidence: 99%

Antileishmanial potential of immunomodulator gallic acid against experimental murine visceral leishmaniasis

Keshav

Goyal

Kaur

2021

Parasite Immunology

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Neglected tropical diseases (NTDs) affect nearly one-sixth of the world's population, and leishmaniasis is one such disease. The eukaryotic protozoan parasite of genus Leishmania with nearly 20 species is known to cause the disease leishmaniasis and is prevalent in nearly hundred countries throughout the world. 1 Female phlebotomine sand flies are transmission vectors of the disease. Parasite species and host immune response determine the disease outcome, and the three major manifestations are cutaneous, visceral and mucocutaneous leishmaniasis. 2 Visceral leishmaniasis (VL) is the deadliest of all the forms and is ranked as one of the world's leading parasitic killers with approximately 600 million people at risk across the globe and 7 th in loss of disability-adjusted life years (DALYs) (DNDi reports). In the Indian subcontinent and Africa, L. donovani is the aetiological agent of VL, while in the Mediterranean Basin, it is caused by L. infantum. 3 According to World Health Organization (WHO 2018), more than 95% of VL cases are clustered in 10 countries: India,

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“…The fluorescent nanoparticles have a 700–750 nm excitation wavelength and an emission of 750–800 nm. In this experiment, rhodamine 123 and Nile Red were used as our fluorescent markers in this experiment (Machado et al., 2021 ). The Nile Red is lipophilic and insoluble in water, mimicking nanoparticles' characteristics.…”

Section: Characterization Of Cationic Nanoparticlesmentioning

confidence: 99%

Gemcitabine cationic polymeric nanoparticles against ovarian cancer: formulation, characterization, and targeted drug delivery

2022

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This study focused on gemcitabine (GTB) delivery of cationic polymeric nanoparticles to treat ovarian cancer in order to promote effective localized delivery and drug retention during biological discharge. To begin, four GTB-loaded polymer nanoparticles were prepared: chitosan nanoparticles (CS-NPs), polysarcosin nanoparticles (PSar-NPs), poly- l -lysine & polysarcosin nanoparticles (PLL-PSar-NPs), and chitosan & polysarcosin nanoparticles (CS-PSar-NPs). Based on preliminary particle size, zeta potential, encapsulation efficiency, DSC, surface morphology, release profiling, and cellular internalization studies using rhodamine 123 and Nile red fluorescent markers, it was hypothesized that CS-PSar-NPs could be the best cationic formulation with strong biocompatibility and anticancer activity against the OVCAR-8 ovarian cancer cell line. To improve effective targeting, cellular penetration, and in vitro cytotoxicity, epidermal growth factor receptor variation III (EGFRvIII) is attached over all four polymeric nanoparticles. Confocal imaging revealed that EGFRvIII-conjugated cationic GTB polymeric nanoparticles had a greater cellular uptake and double internalization capabilities than unconjugated nanoparticles, as well as time-dependent cell entrance. GTB and EGFRvIII-conjugated polymer nanoparticles would have a stronger potential to infiltrate ovarian cancer cells during the first hour of incubation. According to TEM and FTIR findings, EGFRvIII conjugation across the non-target CS-PSar-NP surface was successful, making CS-PSar-NPS-EGFRvIII more target-specific and thus a safer drug delivery candidate for ovarian cancer treatment. Highlights GTB loaded non-target CS-PSar-NPs & active targeted CS-PSar-NPs-EGFRvII developed. SEM, AFM, DSC, particle size, zeta potential, internalization performed for CS-PSar-NPs. MTT & CLSM study confirmed CS-PSar-NPS-EGFRvII was binding specific to OVCAR-8 cells Fabrication of EGFRvII over nanoparticles confirmed by TEM. CS-PSar-NPS-EGFRvII safer candidate for ovarian cancer.

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PF-429242, a Subtilisin Inhibitor, Is Effective in vitro Against Leishmania infantum

Cited by 26 publications

References 55 publications

Effects of a Serine Protease Inhibitor N-p-Tosyl-L-phenylalanine Chloromethyl Ketone (TPCK) on Leishmania amazonensis and Leishmania infantum

Effects of a Serine Protease Inhibitor N-p-Tosyl-L-phenylalanine Chloromethyl Ketone (TPCK) on Leishmania amazonensis and Leishmania infantum

Antileishmanial potential of immunomodulator gallic acid against experimental murine visceral leishmaniasis

Gemcitabine cationic polymeric nanoparticles against ovarian cancer: formulation, characterization, and targeted drug delivery

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