Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2

Nikolaou, Aikaterini; Kokotou, Maroula G.; Vasilakaki, Sofia; Kokotos, George

doi:10.1016/j.bbalip.2018.08.009

Cited by 68 publications

(63 citation statements)

References 146 publications

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“…Although high concentrations of MAFP (67.5 µM) were required to achieve measurable inhibition of CHO cell lysis, this was the first empirical proof that ExoU catalytic activity could be targeted by a small molecule inhibitor. This also validated the assertion that clinical phospholipase inhibitors, developed to target endogenous human phospholipases across a broad spectrum of diseases [100] could potentially have ExoU inhibiting activity. Such compounds could be repurposed to circumvent the pathological consequences of ExoU expression [101].…”

Section: Pharmacological Targeting Of the Bacterial Phospholipase Exousupporting

confidence: 62%

“…The activities of phospholipase A2 enzymes is a contributing factor to various inflammatory pathological conditions, including arthritis, cardiovascular, and autoimmune diseases [100]. Modulation of their catalytic activity has become of major interest to pharmaceutical companies in recent years for the development of novel therapeutics [100]. De novo drug discovery, usually performed in the pharmaceutical industry, is an expensive and long process.…”

Section: Ligand Repurposing Approachesmentioning

confidence: 99%

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Pseudomonas aeruginosa Toxin ExoU as a Therapeutic Target in the Treatment of Bacterial Infections

et al. 2019

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The opportunistic pathogen Pseudomonas aeruginosa employs the type III secretion system (T3SS) and four effector proteins, ExoS, ExoT, ExoU, and ExoY, to disrupt cellular physiology and subvert the host’s innate immune response. Of the effector proteins delivered by the T3SS, ExoU is the most toxic. In P. aeruginosa infections, where the ExoU gene is expressed, disease severity is increased with poorer prognoses. This is considered to be due to the rapid and irreversible damage exerted by the phospholipase activity of ExoU, which cannot be halted before conventional antibiotics can successfully eliminate the pathogen. This review will discuss what is currently known about ExoU and explore its potential as a therapeutic target, highlighting some of the small molecule ExoU inhibitors that have been discovered from screening approaches.

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Section: Pharmacological Targeting Of the Bacterial Phospholipase Exousupporting

confidence: 62%

Section: Ligand Repurposing Approachesmentioning

confidence: 99%

Pseudomonas aeruginosa Toxin ExoU as a Therapeutic Target in the Treatment of Bacterial Infections

et al. 2019

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“…The inflammatory status related to the varicocele may explain this relationship. PLA 2 enzymes are implicated in numerous pathological diseases related to inflammation; the goal of the medicinal chemistry studies will be to develop PLA 2 inhibitors as a new treatment in inflammatory conditions (Nikolaou, Kokotou, Vasilakaki, & Kokotos, 2019). An interplay involving activation of cPLA 2 , inflammation, oxidative stress and phospholipid impairment was also reported in other pathological condition, according to an increase in plasma concentration of cPLA 2 (Qasem, Al-Ayadhi, Al Dera, & El-Ansary, 2017).…”

Section: Discussionmentioning

confidence: 99%

Cytosolic phospholipase A ₂ and F ₂ isoprostanes are involved in semen quality and human infertility—A study on leucocytospermia, varicocele and idiopathic infertility

Collodel

Castellini

Iacoponi³

et al. 2019

Andrologia

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Phospholipase A 2 (PLA 2 ) is involved in eicosanoid release, and F 2 -isoprostanes (F 2 -IsoPs), as free radical-generated eicosanoids released by PLA 2 , are indicators of oxidative stress in different human conditions. This study investigated the interplay between cytosolic PLA 2 (cPLA 2 ), F 2 -IsoPs and sperm features in male infertility, when the involvement of oxidative stress has been reported. Semen evaluation was performed following WHO guidelines, sperm ultrastructure was detected by transmission electron microscopy indicating a fertility index, and the percentages of sperm immaturity, apoptosis and necrosis. In sperm cells and seminal plasma, cPLA 2 levels were determined by immunological method, whereas F 2 -IsoPs by mass spectrometry.Sperm concentration, morphology, vitality and fertility index values were significantly lower in infertile groups compared with fertile men. An increase in sperm apoptosis and necrosis (p < .01), apoptosis (p < .01) and immaturity (p < .001) was detected in leucocytospermia, idiopathic infertility and varicocele, respectively. Seminal cPLA 2 showed the highest value in varicocele group (p < .05), whereas seminal F 2 -IsoPs increased in varicocele (p < .001) and leucocytospermia (p < .05) groups. In the whole population, F 2 -IsoP and cPLA 2 levels were positively correlated (p < .05). On the contrary, F 2 -IsoPs and cPLA 2 were not significantly different when investigated in sperm cells. Our data indicate that fatty acid oxidation/metabolism plays a role in different male reproductive pathological conditions. K E Y W O R D Scytosolic PLA 2 , human semen, leucocytospermia, sperm cells, varicocele

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“…In the past decade, a number of reviews have been published with respect to the structure, genetic aspects, biological roles, disease implications, and specific inhibitors of Lp‐PLA2 . In addition, Lp‐PLA2 has been reviewed as a part of the PLA2 superfamily or PAF‐AHs .…”

Section: Introductionmentioning

confidence: 99%

Lipoprotein‐associated phospholipase A2: The story continues

Huang

Wang

Shen

2019

Medicinal Research Reviews

121

140

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Inflammation is thought to play an important role in the pathogenesis of vascular diseases. Lipoprotein‐associated phospholipase A2 (Lp‐PLA2) mediates vascular inflammation through the regulation of lipid metabolism in blood, thus, it has been extensively investigated to identify its role in vascular inflammation‐related diseases, mainly atherosclerosis. Although darapladib, the most advanced Lp‐PLA2 inhibitor, failed to meet the primary endpoints of two large phase III trials in atherosclerosis patients cotreated with standard medical care, the research on Lp‐PLA2 has not been terminated. Novel pathogenic, epidemiologic, genetic, and crystallographic studies regarding Lp‐PLA2 have been reported recently, while novel inhibitors were identified through a fragment‐based lead discovery strategy. More strikingly, recent clinical and preclinical studies revealed that Lp‐PLA2 inhibition showed promising therapeutic effects in diabetic macular edema and Alzheimer's disease. In this review, we not only summarized the knowledge of Lp‐PLA2 established in the past decades but also emphasized new findings in recent years. We hope this review could be valuable for helping researchers acquire a much deeper insight into the nature of Lp‐PLA2, identify more potent and selective Lp‐PLA2 inhibitors, and discover the potential indications of Lp‐PLA2 inhibitors.

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Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2

Cited by 68 publications

References 146 publications

Pseudomonas aeruginosa Toxin ExoU as a Therapeutic Target in the Treatment of Bacterial Infections

Pseudomonas aeruginosa Toxin ExoU as a Therapeutic Target in the Treatment of Bacterial Infections

Cytosolic phospholipase A ₂ and F ₂ isoprostanes are involved in semen quality and human infertility—A study on leucocytospermia, varicocele and idiopathic infertility

Lipoprotein‐associated phospholipase A2: The story continues

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Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2

Cited by 68 publications

References 146 publications

Pseudomonas aeruginosa Toxin ExoU as a Therapeutic Target in the Treatment of Bacterial Infections

Pseudomonas aeruginosa Toxin ExoU as a Therapeutic Target in the Treatment of Bacterial Infections

Cytosolic phospholipase A 2 and F 2 isoprostanes are involved in semen quality and human infertility—A study on leucocytospermia, varicocele and idiopathic infertility

Lipoprotein‐associated phospholipase A2: The story continues

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Cytosolic phospholipase A ₂ and F ₂ isoprostanes are involved in semen quality and human infertility—A study on leucocytospermia, varicocele and idiopathic infertility