Modulation of peptidases by 2,4-diamine-quinazoline derivative induces cell death in the amitochondriate parasite Trichomonas vaginalis

Weber, Juliana Inês; Rigo, Graziela Vargas; Rocha, Débora Assumpção; Fortes, Isadora S.; Seixas, Adriana; Andrade, Saulo Fernandes de; Tasca, Tiana

doi:10.1016/j.biopha.2021.111611

Cited by 6 publications

(7 citation statements)

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“…Azocasein is one of the most reliable substrates for measuring proteolytic activity, as it has good color stability and no need for chromogenic reagents [ 34 ]. The same methodology used to characterize T. vaginalis peptidases has been used to evaluate the trichomonacidal effects of compounds such as 2,4-diamine-quinazoline derivative [ 27 , 35 ]. As shown in Figure 5 A, trophozoites treated with Cu-phendione had a significant reduction (77.14%) in their ability to degrade the casein substrate compared to untreated parasite cells, demonstrating an important inhibitory effect on the peptidase pool.…”

Section: Resultsmentioning

confidence: 99%

“…T. vaginalis proteolytic activity was evaluated according to Weber et al [ 27 ] using azocasein as substrate. After treatment, protein quantification was performed by the Coomassie blue method [ 28 ] and adjusted to a final concentration of 0.3 mg/mL.…”

Section: Methodsmentioning

confidence: 99%

“…Evaluation of the relative gene expression of T. vaginalis peptidases was performed for the CPs (calpain, cathepsin L and B), MPs (TvMP50 and TvGP63), and aspartic-type peptidase (cathepsin D) [ 13 , 27 ]. Quantitative real-time PCR (qRT-PCR) was used to compare the mRNA levels expressed between trophozoites treated with Cu-phendione and the control without treatment.…”

Section: Methodsmentioning

confidence: 99%

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Peptidases Are Potential Targets of Copper(II)-1,10-Phenanthroline-5,6-dione Complex, a Promising and Potent New Drug against Trichomonas vaginalis

et al. 2023

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Trichomonas vaginalis is responsible for 156 million new cases per year worldwide. When present asymptomatically, the parasite can lead to serious complications, such as development of cervical and prostate cancer. As infection increases the acquisition and transmission of HIV, the control of trichomoniasis represents an important niche for the discovery and development of new antiparasitic molecules. This urogenital parasite synthesizes several molecules that allow the establishment and pathogenesis of infection. Among them, peptidases occupy key roles as virulence factors, and the inhibition of these enzymes has become an important mechanism for modulating pathogenesis. Based on these premises, our group recently reported the potent anti-T. vaginalis action of the metal-based complex [Cu(phendione)3](ClO4)2.4H2O (Cu-phendione). In the present study, we evaluated the influence of Cu-phendione on the modulation of proteolytic activities produced by T. vaginalis by biochemical and molecular approaches. Cu-phendione showed strong inhibitory potential against T. vaginalis peptidases, especially cysteine- and metallo-type peptidases. The latter revealed a more prominent effect at both the post-transcriptional and post-translational levels. Molecular Docking analysis confirmed the interaction of Cu-phendione, with high binding energy (−9.7 and −10.7 kcal·mol−1, respectively) at the active site of both TvMP50 and TvGP63 metallopeptidases. In addition, Cu-phendione significantly reduced trophozoite-mediated cytolysis in human vaginal (HMVII) and monkey kidney (VERO) epithelial cell lineages. These results highlight the antiparasitic potential of Cu-phendione by interaction with important T. vaginalis virulence factors.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Peptidases Are Potential Targets of Copper(II)-1,10-Phenanthroline-5,6-dione Complex, a Promising and Potent New Drug against Trichomonas vaginalis

et al. 2023

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“…Another compound, 2,4-diamine-quinazoline derivative (PH100), was evaluated, and demonstrated anti-T. vaginalis activity and synergistic interaction with MTZ against different isolates. IC 50 values ranged between 14.8 and 50 µM, and MIC values were 80.0-90.0 µM, for a fresh clinical isolate and a long-term-grown ATCC strain, respectively, revealing the effect on function and expression of several trophozoite peptidases related to apoptosis cell death [21]. The in vitro evaluation of N-chlorotaurine (NCT) demonstrated activity against T. vaginalis, of which 5.5 mM NCT (1%) led to the death of 100% parasites in 15 min.…”

Section: Articles: Synthetic Compoundsmentioning

confidence: 98%

Novel Treatment Approaches to Combat Trichomoniasis, a Neglected and Sexually Transmitted Infection Caused by Trichomonas vaginalis: Translational Perspectives

et al. 2022

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The multistep translational science behind new drugs comprehends the entire process through laboratory, clinical, and community observations turned into health interventions. The development of new drug options from discovering targets and leading compounds in basic research for implementing therapeutic guidelines contributes to the emergence of health policies essential for infection control. This review updates the translational research in the scenario of the most common non-viral sexually transmitted infection (STI), trichomoniasis. Paradoxically to its high occurrence, it is considered neglected since notification is not mandatory. It turns into a stable disease with health complications, and receives little emphasis from public health programs to control STI. Although related to curable STIs, the current drugs, metronidazole and tinidazole, present therapeutic failures. The need for new options to treat trichomoniasis is established by basic research studies and patents revealing novel synthetic compounds and natural products presenting anti-Trichomonas vaginalis activities, mainly based on in vitro findings. Clinical trials are still focused on new routes of administration for conventional drugs. In addition, nanotechnology approaches are in their infancy, shedding light on potential possibilities for creating more effective, targeted, and safe delivery systems. Overall, the novel proposed approaches need, in addition to pharmaceutical development and efficacy assessments, to ensure that the quality requirements for their use as medicines are met. It is essential to overcome these issues to cross the “Death Valley” of drug discovery and to advance in the translational science criteria in the trichomoniasis drug development field.

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“…Trichomonas vaginalis is a parasite found in the human vagina and urinary tract ( 49 ). It causes a sexually transmitted infectious disease that may lead to Trichomonas vaginitis, urethritis, pelvic inflammation, premature birth and endometriosis ( 50 ).…”

Section: Phylum Sarcomastigophora Class Zoomastigophoreamentioning

confidence: 99%

The State of Art of Extracellular Traps in Protozoan Infections (Review)

2021

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Protozoan parasite infection causes severe diseases in humans and animals, leading to tremendous economic and medical pressure. Natural immunity is the first line of defence against parasitic infection. Currently, the role of natural host immunity in combatting parasitic infection is unclear, so further research on natural host immunity against parasites will provide a theoretical basis for the prevention and treatment of related parasitic diseases. Extracellular traps (ETs) are an important natural mechanism of immunity involving resistance to pathogens. When immune cells such as neutrophils and macrophages are stimulated by external pathogens, they release a fibrous network structure, consisting mainly of DNA and protein, that can capture and kill a variety of extracellular pathogenic microorganisms. In this review, we discuss the relevant recently reported data on ET formation induced by protozoan parasite infection, including the molecular mechanisms involved, and discuss the role of ETs in the occurrence and development of parasitic diseases.

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Modulation of peptidases by 2,4-diamine-quinazoline derivative induces cell death in the amitochondriate parasite Trichomonas vaginalis

Cited by 6 publications

References 47 publications

Peptidases Are Potential Targets of Copper(II)-1,10-Phenanthroline-5,6-dione Complex, a Promising and Potent New Drug against Trichomonas vaginalis

Peptidases Are Potential Targets of Copper(II)-1,10-Phenanthroline-5,6-dione Complex, a Promising and Potent New Drug against Trichomonas vaginalis

Novel Treatment Approaches to Combat Trichomoniasis, a Neglected and Sexually Transmitted Infection Caused by Trichomonas vaginalis: Translational Perspectives

The State of Art of Extracellular Traps in Protozoan Infections (Review)

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