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

Machado, Patrícia de A.; Gomes, Pollyanna S.; Carneiro, Monique P. D.; Midlej, Victor; Coimbra, Elaine S.; de Matos Guedes, Herbert L.

doi:10.3390/pharmaceutics14071373

Open AccessArticle

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

by

Patrícia de A. Machado

^1,2,3,†,

Pollyanna S. Gomes

^1,2,†

,

Monique P. D. Carneiro

^2,4,

Victor Midlej

⁵

,

Elaine S. Coimbra

^3,* and

Herbert L. de Matos Guedes

^1,2,4,*

¹

Laboratório de Imunologia Clínica, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz—Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil

²

Laboratório de Imunobiotecnologia, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil

³

Núcleo de Pesquisas em Parasitologia (NUPEP), Instituto de Ciências Biológicas, Universidade Federal de Juiz de Fora, Juiz de Fora 36036-900, MG, Brazil

⁴

Laboratório de Imunofarmacologia, Instituto de Biofísica Carlos Chagas Filho (IBCCF), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil

⁵

Laboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz—Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Pharmaceutics 2022, 14(7), 1373; https://doi.org/10.3390/pharmaceutics14071373

Submission received: 31 March 2022 / Revised: 29 April 2022 / Accepted: 2 May 2022 / Published: 29 June 2022

(This article belongs to the Special Issue Development of Novel Pharmaceuticals for the Treatment of Parasitic Diseases)

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Abstract

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.

Keywords: serine proteases; TPCK; leishmaniasis; Leishmania amazonensis; Leishmania infantum

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MDPI and ACS Style

Machado, P.d.A.; Gomes, P.S.; Carneiro, M.P.D.; Midlej, V.; Coimbra, E.S.; de Matos Guedes, H.L. Effects of a Serine Protease Inhibitor N-p-Tosyl-L-phenylalanine Chloromethyl Ketone (TPCK) on Leishmania amazonensis and Leishmania infantum. Pharmaceutics 2022, 14, 1373. https://doi.org/10.3390/pharmaceutics14071373

AMA Style

Machado PdA, Gomes PS, Carneiro MPD, Midlej V, Coimbra ES, de Matos Guedes HL. Effects of a Serine Protease Inhibitor N-p-Tosyl-L-phenylalanine Chloromethyl Ketone (TPCK) on Leishmania amazonensis and Leishmania infantum. Pharmaceutics. 2022; 14(7):1373. https://doi.org/10.3390/pharmaceutics14071373

Chicago/Turabian Style

Machado, Patrícia de A., Pollyanna S. Gomes, Monique P. D. Carneiro, Victor Midlej, Elaine S. Coimbra, and Herbert L. de Matos Guedes. 2022. "Effects of a Serine Protease Inhibitor N-p-Tosyl-L-phenylalanine Chloromethyl Ketone (TPCK) on Leishmania amazonensis and Leishmania infantum" Pharmaceutics 14, no. 7: 1373. https://doi.org/10.3390/pharmaceutics14071373

APA Style

Machado, P. d. A., Gomes, P. S., Carneiro, M. P. D., Midlej, V., Coimbra, E. S., & de Matos Guedes, H. L. (2022). Effects of a Serine Protease Inhibitor N-p-Tosyl-L-phenylalanine Chloromethyl Ketone (TPCK) on Leishmania amazonensis and Leishmania infantum. Pharmaceutics, 14(7), 1373. https://doi.org/10.3390/pharmaceutics14071373

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

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