Leishmania donovani Parasites Are Inhibited by the Benzoxaborole AN2690 Targeting Leucyl-tRNA Synthetase

Manhas, Reetika; Tandon, Smriti; Sen, Shib Sankar; Tiwari, Neha; Munde, Manoj; Madhubala, Rentala

doi:10.1128/aac.00079-18

Cited by 24 publications

(22 citation statements)

References 43 publications

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“…Compound 89 (C89) is a kind of benzoborazole. C89, 7-formyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole, was recently synthesized based on the structure of AN2690 [33,34], 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole, an antifungal agent that inactivates fungalleucyl-tRNA synthetase [35]. C89 is a novel compound, and have been no reports about the function of C89 in the autophagy of FGSCs or other kinds of cells.…”

Section: Introductionmentioning

confidence: 99%

C89 Induces Autophagy of Female Germline Stem Cells via Inhibition of the PI3K-Akt Pathway In Vitro

Tian

et al. 2019

Cells

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Postnatal female germline stem cells (FGSCs) are a type of germline stem cell with self-renewal ability and the capacity of differentiation toward oocyte. The proliferation, differentiation, and apoptosis of FGSCs have been researched in recent years, but autophagy in FGSCs has not been explored. This study investigated the effects of the small-molecule compound 89 (C89) on FGSCs and the underlying molecular mechanism in vitro. Cytometry, Cell Counting Kit-8 (CCK8), and 5-ethynyl-2’-deoxyuridine (EdU) assay showed that the number, viability, and proliferation of FGSCs were significantly reduced in C89-treated groups (0.5, 1, and 2 µM) compared with controls. C89 had no impact on FGSC apoptosis or differentiation. However, C89 treatment induced the expression of light chain 3 beta II (LC3BII) and reduced the expression of sequestosome-1 (SQSTM1) in FGSCs, indicating that C89 induced FGSC autophagy. To investigate the mechanism of C89-induced FGSC autophagy, RNA-seq technology was used to compare the transcriptome differences between C89-treated FGSCs and controls. Bioinformatics analysis of the sequencing data indicated a potential involvement of the phosphatidylinositol 3 kinase and kinase Akt (PI3K-Akt) pathway in the effects of C89′s induction of autophagy in FGSCs. Western blot confirmed that levels of p-PI3K and p-Akt were significantly reduced in the C89- or LY294002 (PI3K inhibitor)-treated groups compared with controls. Moreover, we found cooperative functions of C89 and LY294002 in inducing FGSC autophagy through suppressing the PI3K-Akt pathway. Taken together, this research demonstrates that C89 can reduce the number, viability, and proliferation of FGSCs by inducing autophagy. Furthermore, C89 induced FGSC autophagy by inhibiting the activity of PI3K and Akt. The PI3K-Akt pathway may be a target to regulate FGSC proliferation and death.

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Section: Introductionmentioning

confidence: 99%

C89 Induces Autophagy of Female Germline Stem Cells via Inhibition of the PI3K-Akt Pathway In Vitro

Tian

et al. 2019

Cells

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“…In a new drug screening process, leucyl-tRNA synthetase from L. donovani ( Ld LRS) was selected as a potential drug target for Leishmania . This enzyme plays an essential role in the viability of this pathogenic organism and appears to be indispensable for its survival in vitro [ 112 ]. Compound 2 ( Figure 1 ) exhibited anti-leishmanial activity against both promastigote and amastigote stages, in vitro, as well as in vivo in BALB/c mice, as shown in Figure 13 A.…”

Section: Neglected Tropical Diseases (Ntd)mentioning

confidence: 99%

Organoboron Compounds: Effective Antibacterial and Antiparasitic Agents

Coghi

Zhu²,

Xie³

et al. 2021

Molecules

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The unique electron deficiency and coordination property of boron led to a wide range of applications in chemistry, energy research, materials science and the life sciences. The use of boron-containing compounds as pharmaceutical agents has a long history, and recent developments have produced encouraging strides. Boron agents have been used for both radiotherapy and chemotherapy. In radiotherapy, boron neutron capture therapy (BNCT) has been investigated to treat various types of tumors, such as glioblastoma multiforme (GBM) of brain, head and neck tumors, etc. Boron agents playing essential roles in such treatments and other well-established areas have been discussed elsewhere. Organoboron compounds used to treat various diseases besides tumor treatments through BNCT technology have also marked an important milestone. Following the clinical introduction of bortezomib as an anti-cancer agent, benzoxaborole drugs, tavaborole and crisaborole, have been approved for clinical use in the treatments of onychomycosis and atopic dermatitis. Some heterocyclic organoboron compounds represent potentially promising candidates for anti-infective drugs. This review highlights the clinical applications and perspectives of organoboron compounds with the natural boron atoms in disease treatments without neutron irradiation. The main topic focuses on the therapeutic applications of organoboron compounds in the diseases of tuberculosis and antifungal activity, malaria, neglected tropical diseases and cryptosporidiosis and toxoplasmosis.

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“…The weight of the spleen was measured and dabbed imprints on glass slides were made, followed by fixation with 100% methanol and Giemsa staining. Infection was monitored microscopically by using Giemsa-stained imprints, in which parasite burdens were measured by counting the numbers of amastigotes per 500 spleen nuclei and multiplying by the spleen weight (mg) (Leishman-Donovan units [LDU]) (81). The results for the treated and untreated groups were compared.…”

Section: Sds-page and Western Blottingmentioning

confidence: 99%

TCP1γ Subunit Is Indispensable for Growth and Infectivity of Leishmania donovani

Yadav

Kuldeep

Siddiqi

et al. 2020

Antimicrob Agents Chemother

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T-complex protein-1 (TCP1) is a ubiquitous group II chaperonin and is known to fold various proteins, such as actin and tubulin. In Leishmania donovani, the γ subunit of TCP1 (LdTCP1γ) has been cloned and characterized. It forms a high-molecular-weight homo-oligomeric complex that performs ATP-dependent protein folding. In the present study, we evaluated the essentiality of the LdTCP1γ gene. Gene replacement studies indicated that LdTCP1γ is essential for parasite survival. The LdTCP1γ single-allele-replacement mutants exhibited slowed growth and decreased infectivity in mouse macrophages compared to the growth and infectivity of the wild-type parasites. Modulation of LdTCP1γ expression in promastigotes also modulated cell cycle progression. Suramin, an antitrypanosomal drug, not only inhibited the luciferase refolding activity of the recombinant LdTCP1γ (rLdTCP1γ) homo-oligomeric complex but also exhibited potential antileishmanial efficacy both in vitro and in vivo. The interaction of suramin and LdTCP1γ was further validated by isothermal titration calorimetry. The study suggests LdTCP1γ as a potential drug target and also provides a framework for the development of a new class of drugs.

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Leishmania donovani Parasites Are Inhibited by the Benzoxaborole AN2690 Targeting Leucyl-tRNA Synthetase

Cited by 24 publications

References 43 publications

C89 Induces Autophagy of Female Germline Stem Cells via Inhibition of the PI3K-Akt Pathway In Vitro

C89 Induces Autophagy of Female Germline Stem Cells via Inhibition of the PI3K-Akt Pathway In Vitro

Organoboron Compounds: Effective Antibacterial and Antiparasitic Agents

TCP1γ Subunit Is Indispensable for Growth and Infectivity of Leishmania donovani

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