New strategies for combating fungal infections: Inhibiting inositol lipid signaling by targeting Sec14 phosphatidylinositol transfer proteins

Bankaitis, Vytas A.; Tripathi, Ashutosh; Chen, Xiaoru; Igumenova, Tatyana I.

doi:10.1016/j.jbior.2022.100891

Cited by 5 publications

(9 citation statements)

References 84 publications

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“…Sensitivity of a fungal Sec14 to validated SMIs is predicted by (i) the set of Sec14 residues involved in coordinating PtdCho headgroup-binding ( i.e. , the PtdCho-binding barcode ( 20 ) and (ii) the Val 154 Val 155 (VV)-motif ( 21 , 25 , 26 ). Most virulent fungi express Sec14 PITPs with altered VV-motifs that substitute at least one of the Val residues — typically with at least one bulkier amino acid.…”

Section: Discussionmentioning

confidence: 99%

“…It is on this basis that the membrane trafficking activities of Sec14 orthologs are essential for the virulence of pathogenic fungi of clinical significance ( 18 , 19 ). When coupled with demonstrations that small molecules directly inhibit yeast Sec14 with exquisite specificity with no obvious off-target effects ( 20 , 21 , 22 ), the emerging data identify Sec14 as an attractive target for development of next-generation antifungal drugs ( 23 , 24 , 25 , 26 ). This attractiveness is further justified by the fact that mammalian Sec14-like proteins lack the motifs critical for binding to presently validated small molecule inhibitors directed against fungal Sec14 PITPs ( 25 , 26 ).…”

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confidence: 99%

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Mechanisms by which small molecules of diverse chemotypes arrest Sec14 lipid transfer activity

Chen

Poudel

Hong

et al. 2023

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Mechanisms by which small molecules of diverse chemotypes arrest Sec14 lipid transfer activity

Chen

Poudel

Hong

et al. 2023

Journal of Biological Chemistry

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“…In that regard, the rigorous validation of Sec14 as specific target of SMIs of multiple chemotypes identifies fungal Sec14 orthologs as promising targets for development of new anti-fungal drugs. Whether a fungal Sec14 will display sensitivity to the presently validated SMIs is quite reliably predicted by two Sec14 elements – the PtdCho-binding signature (or barcode), and the Val 154 Val 155 (VV)- motif that contributes to the contours of the PtdCho headgroup-binding environment (Khan et al, 2016; Khan et al, 2021; Bankaitis et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…This exchange cycle is central to PtdIns-4-P signaling, but the protein and lipid dynamics associated with it are not at all understood. Second, fungal Sec14s are emerging as promising new targets for development of urgently needed next-generation anti-mycotics (Nile et al, 2014;Khan et al, 2021: Bankaitis et al, 2022. Sec14-directed SMIs serve as valuable lead compounds for such efforts.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms by Which Small Molecule Inhibitors Arrest Sec14 Phosphatidylinositol Transfer Protein Activity

Chen

Poudel

Hong

et al. 2022

Preprint

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Phosphatidylinositol transfer proteins (PITPs) promote phosphoinositide signaling by enhancing phosphatidylinositol (PtdIns) 4-OH kinase activities in producing signaling pools of PtdIns-4-phosphate. As such, PITPs are key regulators of lipid signaling in eukaryotic cells. While the PITP phospholipid exchange cycle is the engine that stimulates PtdIns 4-OH kinase activity, the protein and lipid dynamics associated with this critical process are not understood. Herein, we use an integrative structural approach that takes advantage of small molecule inhibitors (SMIs) directed against the major yeast PITP (Sec14) to gain new insights into the mechanics of the Sec14 phospholipid exchange cycle from the perspective of protein, phospholipid and SMI dynamics. Moreover, as Sec14 has emerged as an attractive target for next-generation antifungal drugs, the structures of Sec14 bound to SMIs of four different chemotypes reported in this study provide critical information required for structure-based design of next-generation lead compounds that target Sec14 PITPs of virulent fungi.

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“…Fungal infection causes significant implications, threatening date palms with high morbidity and mortality every year worldwide. Therefore, new antifungal inhibitors must be discovered urgently, especially those with new modes of action, low toxicity, and bioavailability, and are effective for responsive and drug-resistant fungi [10][11][12][13][14][15]. Due to their biological activity and chemical properties in recent years, fused heterocyclic compounds containing bridgehead nitrogen or oxygen donor atoms have drawn further interest.…”

Section: Introductionmentioning

confidence: 99%

An Insight into All Tested Small Molecules against Fusarium oxysporum f. sp. Albedinis: A Comparative Review

et al. 2022

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Bayoud disease affects date palms in North Africa and the Middle East, and many researchers have used various methods to fight it. One of those methods is the chemical use of synthetic compounds, which raises questions centred around the compounds and common features used to prepare targeted molecules. In this review, 100 compounds of tested small molecules, collected from 2002 to 2022 in Web of Sciences, were divided into ten different classes against the main cause of Bayoud disease pathogen Fusarium oxysporum f. sp. albedinis (F.o.a.) with structure–activity relationship (SAR) interpretations for pharmacophore site predictions as (δ−···δ−), where 12 compounds are the most efficient (one compound from each group). The compounds, i.e., (Z)-1-(1.5-Dimethyl-1H-pyrazole-3-yl)-3-hydroxy but-2-en-1-one 7, (Z)-3-(phenyl)-1-(1,5-dimethyl-1H-pyrazole-3-yl)-3-hydroxyprop-2-en-1-one 23, (Z)-1-(1,5-Dimethyl-1H-pyrazole-3-yl)-3-hydroxy-3-(pyridine-2-yl)prop-2-en-1-one 29, and 2,3-bis-[(2-hydroxy-2-phenyl)ethenyl]-6-nitro-quinoxaline 61, have antifungal pharmacophore sites (δ−···δ−) in common in N1---O4, whereas other compounds have only one δ− pharmacophore site pushed by the donor effect of the substituents on the phenyl rings. This specificity interferes in the biological activity against F.o.a. Further understanding of mechanistic drug–target interactions on this subject is currently underway.

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New strategies for combating fungal infections: Inhibiting inositol lipid signaling by targeting Sec14 phosphatidylinositol transfer proteins

Cited by 5 publications

References 84 publications

Mechanisms by which small molecules of diverse chemotypes arrest Sec14 lipid transfer activity

Mechanisms by which small molecules of diverse chemotypes arrest Sec14 lipid transfer activity

Mechanisms by Which Small Molecule Inhibitors Arrest Sec14 Phosphatidylinositol Transfer Protein Activity

An Insight into All Tested Small Molecules against Fusarium oxysporum f. sp. Albedinis: A Comparative Review

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