The protein 14-3-3: A functionally versatile molecule in Giardia duodenalis

Lalle, Marco; Fiorillo, Annarita

doi:10.1016/bs.apar.2019.08.002

Cited by 4 publications

(5 citation statements)

References 156 publications

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“…For example, Shi has recently conducted a virtual screening on the Taiwan natural product database containing more than 20,000 small molecule compounds extracted from 453 Chinese medicine against the crystal structure of 14-3-3σ protein (PDB: 1YZ5). Upon molecular dynamic simulations on the top ranked hits from virtual screening, two compounds, 85531185 (21) and 95911592 (22) (Figure 8c), which contain 16-membered macrocycle and 21-membered macrocycle, respectively, have been proposed to be potential 14-3-3σ inhibitors. Nevertheless, although these compounds were reported to bind in the amphipathic binding groove of 14-3-3σ with strong affinity (with estimated free energy binding values of −10.71 and −15.10 kcal/mol, respectively), their in vitro inhibitory activities however remain to be tested [116].…”

Section: Non-phosphonate-type Inhibitors Of 14-3-3σmentioning

confidence: 99%

“…The 14-3-3 proteins are also classified as phosphoserine/phosphothreonine (pSer/pThr)recognition proteins, as they generally exert their activity through binding to the phosphoserine/ phosphothreonine-containing motifs of a multitude of molecules with various functions such as kinases, phosphatases, transmembrane receptors, and transcription factors [2,[20][21][22]. In general, there are two high-affinity phosphorylation-dependent binding motifs that are recognized by the amphipathic mode I, Figure 1a) and Arg-Xaa-Xaa-Xaa-pSer/Thr-Xaa-Pro (R-X-X-X-pS/T-X-P, mode II, Figure 1b), where X is any amino acid and pS/T represents phosphorylated serine or threonine [23][24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

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14-3-3σ and Its Modulators in Cancer

Aljabal

Yap

2020

Pharmaceuticals

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14-3-3σ is an acidic homodimer protein with more than one hundred different protein partners associated with oncogenic signaling and cell cycle regulation. This review aims to highlight the crucial role of 14-3-3σ in controlling tumor growth and apoptosis and provide a detailed discussion on the structure–activity relationship and binding interactions of the most recent 14-3-3σ protein-protein interaction (PPI) modulators reported to date, which has not been reviewed previously. This includes the new fusicoccanes stabilizers (FC-NAc, DP-005), fragment stabilizers (TCF521-123, TCF521-129, AZ-003, AZ-008), phosphate-based inhibitors (IMP, PLP), peptide inhibitors (2a–d), as well as inhibitors from natural sources (85531185, 95911592). Additionally, this review will also include the discussions of the recent efforts by a different group of researchers for understanding the binding mechanisms of existing 14-3-3σ PPI modulators. The strategies and state-of-the-art techniques applied by various group of researchers in the discovery of a different chemical class of 14-3-3σ modulators for cancer are also briefly discussed in this review, which can be used as a guide in the development of new 14-3-3σ modulators in the near future.

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Section: Non-phosphonate-type Inhibitors Of 14-3-3σmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

14-3-3σ and Its Modulators in Cancer

Aljabal

Yap

2020

Pharmaceuticals

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“…In the solved structure (2B4T) [18] of the parasite glyceraldehyde-3-phosphate dehydrogenase (PfGAPDH; PF3D7_1462800), the modified Cys58 locates on the enzyme surface, away from the catalytic site (Supplementary Figure S6). In the structure model (AF-C0H4V6-F1) of Pf14-3-3I protein (PF3D7_0818200) [19][20][21], the modified Cys149 resides in loop 5, encompassing alpha helices 5 and 6 [22], at one edge of the phosphorylated target binding groove (Supplementary Figure S7). In our automated molecular model of PfCDC48 (PF3D7_0619400), the Cys98 modified by 1 resides in the N-terminal domain, buried in the interface between the N-and the first ATPase domain, D1 [23,24] (Supplementary Figure S8).…”

Section: Exposure To 1 But Not To Its Amine Analogue Results In the Formation Of Adducts With Specific Cysteine Residues Of P Falciparum mentioning

confidence: 99%

“…The Pf14-3-3I belongs to a family of eukaryotic dimeric adaptor proteins binding to hundreds of proteins on specific phosphoserine/phosphothreonine binding motifs, thus being involved in the regulation of multiple key biological processes [34]. In the Pf14-3-3I identified here, one of the two P. falciparum structurally conserved isoforms [19][20][21], the modified Cys149 resides in loop 5, encompassing alpha helices 5 and 6 [22], a protein portion shown to contribute to structural diversity between plant 14-3-3 subgroups and therefore possibly involved in specificity for Pf14-3-3/target binding [35]. In PfCDC48, whose P. berghei orthologue inhibition affects the zygote to ookinete transition and blocks parasite transmission to mosquito [36], the localization of the modified Cys98 in the interface between the N-and D1-domains could possibly lead to conformational changes [23,24], as suggested by the consequence of point mutations in this region of the human CDC48 [37].…”

Section: Discussionmentioning

confidence: 97%

The Nitrobenzoxadiazole Derivative NBDHEX Behaves as Plasmodium falciparum Gametocyte Selective Inhibitor with Malaria Parasite Transmission Blocking Activity

et al. 2022

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This work describes the activity of 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (NBDHEX) and of its newly identified carboxylic acid metabolite on the human malaria parasite Plasmodium falciparum. NBDHEX has been previously identified as a potent cytotoxic agent against murine and human cancer cells as well as towards the protozoan parasite Giardia duodenalis. We show here that NBDHEX is active in vitro against all blood stages of P. falciparum, with the rare feature of killing the parasite stages transmissible to mosquitoes, the gametocytes, with a 4-fold higher potency than that on the pathogenic asexual stages. This activity importantly translates into blocking parasite transmission through the Anopheles vector in mosquito experimental infections. A mass spectrometry analysis identified covalent NBDHEX modifications in specific cysteine residues of five gametocyte proteins, possibly associated with its antiparasitic effect. The carboxylic acid metabolite of NBDHEX retains the gametocyte preferential inhibitory activity of the parent compound, making this novel P. falciparum transmission-blocking chemotype at least as a new tool to uncover biological processes targetable by gametocyte selective drugs. Both NBDHEX and its carboxylic acid metabolite show very limited in vitro cytotoxicity on VERO cells. This result and previous evidence that NBDHEX shows an excellent in vivo safety profile in mice and is orally active against human cancer xenografts make these molecules potential starting points to develop new P. falciparum transmission-blocking agents, enriching the repertoire of drugs needed to eliminate malaria.

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“…Giardia ( G. ) duodenalis , commonly named G. lamblia or G. intestinalis , is a parasitic protozoan that parasitizes the small intestine of a variety of mammals causing giardiasis (Lalle and Hanevik, 2018 ). Giardiasis is a disease that induces fatigue, soft stool, abdominal cramps, vomiting and dehydration (Lalle and Fiorillo, 2019 ); the severity of infection depends on the age and immune conditions of the infected host (Leung et al 2019 ). Giardiasis is a self-limiting illness and most often, infections are asymptomatic.…”

Section: Introductionmentioning

confidence: 99%

Role of anti-Giardia recombinant cyst wall protein IgG polyclonal antibodies in diagnosis and protection

et al. 2022

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Giardia duodenalis (G. duodenalis) is an infectious protozoan that has a global distribution especially in the hot climate. Around 200 million people are infected worldwide annually by Giardia, but infection is not always accompanied by symptoms, especially in endemic countries. Using traditional microscopy techniques in diagnosis, both in stool and water samples were less sensitive when compared to immunological methods; and the need for new diagnostic methods was necessary. Also, protection from infection is required in endemic areas. Therefore, the study aimed to produce anti- G. duodenalis IgG polyclonal antibodies (pAbs) by immunizing rabbit by G. duodenalis cyst recombinant protein. The produced antibodies were evaluated in the detection of G. duodenalis antigens in patients’ stool and water samples from endemic areas across River Nile; where pAbs were used as a coating and a peroxidase conjugate antibody in sandwich ELISA. Moreover, pAbs were tested for the protection of mice from giardiasis. Sandwich ELISA using pAb has succeeded in the detection of G. duodenalis coproantigens in stool samples by a sensitivity of 97% and a specificity of 92.72%. Moreover, G. duodenalis cyst was detected in only seven water samples by ordinary microscopy; while sandwich ELISA revealed nineteen positive results. IgG pAb (1/200 µg/ml) protected mice from giardiasis; which was evident from the reduction in cysts and trophozoites numbers. We recommended the use of sandwich ELISA to monitor water quality, investigate environmental contamination and diagnosis in patients' stools. The pAbs can be prepared in large amount and used in field diagnosis and protection. This will help in the early diagnosis of G. duodenalis in water, which in turn can control outbreaks in rural areas.

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The protein 14-3-3: A functionally versatile molecule in Giardia duodenalis

Cited by 4 publications

References 156 publications

14-3-3σ and Its Modulators in Cancer

14-3-3σ and Its Modulators in Cancer

The Nitrobenzoxadiazole Derivative NBDHEX Behaves as Plasmodium falciparum Gametocyte Selective Inhibitor with Malaria Parasite Transmission Blocking Activity

Role of anti-Giardia recombinant cyst wall protein IgG polyclonal antibodies in diagnosis and protection

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