Structure–activity relationship and conformational studies of the natural product cyclic depsipeptides YM-254890 and FR900359

Zhang, Hang; Nielsen, Alexander L.; Boesgaard, Michael W.; Harpsøe, Kasper; Daly, Norelle L.; Xiong, Xiaofeng; Underwood, Christina Rye; Haugaard‐Kedström, Linda M.; Bräuner‐Osborne, Hans; Gloriam, David E.; Strømgaard, Kristian

doi:10.1016/j.ejmech.2018.07.023

Cited by 27 publications

(56 citation statements)

References 34 publications

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“…b, Inhibition of the adenosine diphosphate (ADP)‐induced platelet aggregation in human platelet‐rich plasma . c, d, and e, Inhibition of carbachol‐induced inositol monophosphate (IP 1 ) production in Chinese hamster ovary (CHO) cells that stably express the M 1 muscarinic receptor in different papers: (c) from Xiong et al, (d) from Zhang et al and Xiong et al, and (e) from Reher et al Equipotent analogs are highlighted (pink). The chemical structures were determined by mass spectrometry, one‐ and two‐dimensional nuclear magnetic resonance (NMR) spectrum analysis, chiral high‐performance liquid chromatography (HPLC), Marfey's analysis, high‐resolution mass spectroscopy (HRMS), infrared spectroscopy (IR), and optical rotation.…”

Section: Selective Gq Inhibitorsmentioning

confidence: 99%

“…d, Inhibition of the adenosine diphosphate (ADP)‐induced platelet aggregation in vitro . e, f, g, h, i, and j, Inhibition of carbachol‐induced IP 1 production in Chinese hamster ovary (CHO) cells that stably express the M 1 muscarinic receptor in different papers: (e) from Xiong et al, (f) from Xiong et al, (g) from Zhang et al, (h) from Zhang et al, (i) from Reher et al, and (j) from Zhang…”

Section: Selective Gq Inhibitorsmentioning

confidence: 99%

“…Subsequently, the versatility of the synthetic methodology was demonstrated by the synthesis of more than 30 structurally and stereochemically diverse analogs, which allowed for systematic structure‐activity relationship (SAR) studies of YM‐254890 that focus on the modification of key structural elements such as (i) the N ‐MeDha residue (YM‐385780 ( 7 ), YM‐385781 ( 8 ), YM‐19 to YM‐25 ( 9 ‐ 15 ), Figure ), (ii) the backbone (YM‐1 to YM‐5 ( 16 ‐ 20 ), Figure ), (iii) key β‐HyLeu moieties (YM‐6 to YM‐9 ( 21 ‐ 24 ), YM‐10 ( 2 , also known as YM‐254891), Figures a and ), (iv) side‐chains of N ‐MeAla and Ala (YM‐11 to YM‐18 ( 25‐32 ), Figure ), and (v) side chains of Thr and the N ‐acyl group of β‐HyLeu‐1 (YM‐26 to YM‐30 ( 33 ‐ 37 ), Figure ) . These analogs have highlighted how the bulkiness, stereochemistry and electron density of each amino acid in YM‐254890 influence G q inhibitory potency and selectivity.…”

Section: Selective Gq Inhibitorsmentioning

confidence: 99%

“…C, REMD cluster of analog 31 (teal carbons) superimposed with the cluster of the proposed minor conformer of YM‐254890 (beige carbons) with Thr interacting as the major internal hydrogen bond donor. Figures adapted from Xiong et al and Zhang et al [Color figure can be viewed at wileyonlinelibrary.com]…”

Section: Selective Gq Inhibitorsmentioning

confidence: 99%

“…Crystallization is also performed under non‐physiological conditions at cryogenic temperatures. Hence conformational studies of YM‐254890 in aqueous solution by applying variable temperature 1 H‐NMR spectroscopy together with replica exchange molecular dynamics (REMD) of selected analogs has been used to probe the intramolecular hydrogen‐bonding profile and to reveal the conformational landscape and B), which exists in one conformer in CDCl 3 and acts as a potent G q inhibitor (positive control).…”

Section: Selective Gq Inhibitorsmentioning

confidence: 99%

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Recent achievements in developing selective G_q inhibitors

Zhang

Nielsen

Strømgaard

2019

Medicinal Research Reviews

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G proteins are key mediators of G protein‐coupled receptor (GPCR) signaling, facilitating a plethora of important physiological processes. The role of G proteins is much less understood than other aspects of GPCR function, which is largely due to the shortage of potent and selective G protein inhibitors. The natural cyclic depsipeptides YM‐254890 and FR900359 are two of the very few known selective inhibitors of the Gq subfamily, and are used as unique pharmacological tools in the study of G q‐mediated signaling. Moreover, a peptide‐based G protein antagonist‐2A (GP‐2A), a 27‐residue peptide (27mer(I860A)) derived from phospholipase C‐β3 (PLC‐β3), and the small molecule BIM‐46187 have also been characterized as selective G q inhibitors within the past 5 years. In this review, we highlight the recent development in chemical syntheses, characterization, and mechanism of action of these selective G q inhibitors. The development and application of G q‐selective inhibitors will expand our knowledge of the structure and function of G protein‐mediated signaling, shed light on the development of inhibitors for other G protein classes, and feed in to drug discovery for diseases where G proteins are implicated, including various forms of cancer.

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Section: Selective Gq Inhibitorsmentioning

confidence: 99%

Section: Selective Gq Inhibitorsmentioning

confidence: 99%

Section: Selective Gq Inhibitorsmentioning

confidence: 99%

Section: Selective Gq Inhibitorsmentioning

confidence: 99%

Section: Selective Gq Inhibitorsmentioning

confidence: 99%

See 3 more Smart Citations

Recent achievements in developing selective G_q inhibitors

Zhang

Nielsen

Strømgaard

2019

Medicinal Research Reviews

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A Specialized Dehydrogenase Provides l‐Phenyllactate for FR900359 Biosynthesis

et al. 2021

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d-Phenyllactate (PLA) is a component of the selective Gq protein inhibitor and nonribosomal cyclic depsipeptide FR900359 (FR). Here we report a detailed biochemical investigation of PLA biosynthesis and its incorporation into the natural product FR. The enzyme FrsC, member of the lactate/ malate dehydrogenase superfamily, was shown to catalyze the formation of l-PLA from phenylpyruvate. FrsC was kinetically characterized and its substrate specificity determined. Incorporation of l-PLA was probed by assaying the adenylation domain FrsE-A3 and feeding studies with a Chromobacterium vaccinii ΔfrsC mutant, confirming preferred activation of l-PLA followed by on-line epimerization to d-PLA. Finally, detailed bioinformatic analyses of FrsC revealed its close relation to malate dehydrogenases from primary metabolism and suggest extensions in the substrate binding loop to be responsible for its adaptation to accepting larger aromatic substrates with high specificity.

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Condensation Domain Editing of the FR900359 Assembly Line Yields a Novel Analog Amenable to Late‐Stage Functionalization

Pistorius,

Richard,

Buntin

et al. 2024

ChemBioChem

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The natural product FR900359 (FR) has generated significant attention lately, due to its characteristics as potent and selective inhibitor of Gq/11 mediated signal transduction of associated G protein‐coupled receptors (GPCRs). This makes FR both a widely used pharmacological tool compound and a lead molecule for targeted cancer therapy. The exploration of structure‐activity‐relationship (SAR) of the scaffold by total synthesis has been complicated by its structural complexity and its incompatibility with standard approaches of solid‐phase peptide synthesis. Options for late‐stage functionalization of FR are limited due to a lack of tractable functional groups. Here we present a mixed approach combining i) genetic engineering of the FR‐assembly line in Chromobacterium vaccinii, to obtain a novel FR analog featuring a primary amine, with ii) its subsequent synthetic modification and biological profiling for further SAR exploration of the FR scaffold.

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Structure–activity relationship and conformational studies of the natural product cyclic depsipeptides YM-254890 and FR900359

Cited by 27 publications

References 34 publications

Recent achievements in developing selective G_q inhibitors

Recent achievements in developing selective G_q inhibitors

A Specialized Dehydrogenase Provides l‐Phenyllactate for FR900359 Biosynthesis

Condensation Domain Editing of the FR900359 Assembly Line Yields a Novel Analog Amenable to Late‐Stage Functionalization

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Structure–activity relationship and conformational studies of the natural product cyclic depsipeptides YM-254890 and FR900359

Cited by 27 publications

References 34 publications

Recent achievements in developing selective Gq inhibitors

Recent achievements in developing selective Gq inhibitors

A Specialized Dehydrogenase Provides l‐Phenyllactate for FR900359 Biosynthesis

Condensation Domain Editing of the FR900359 Assembly Line Yields a Novel Analog Amenable to Late‐Stage Functionalization

Contact Info

Product

Resources

About

Recent achievements in developing selective G_q inhibitors

Recent achievements in developing selective G_q inhibitors