Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor

Cunha, Micael Rodrigues; Bhardwaj, Rajesh; Carrel, Aline Lucie; Lindinger, Sonja; Romanin, Christoph; Parise-Filho, Roberto; Hediger, Matthias A.; Reymond, Jean‐Louis

doi:10.1039/d0md00145g

Cited by 24 publications

(22 citation statements)

References 49 publications

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“…S7C). We also tested the effect on Cd 2+ influx of the recently synthesized PCHPDs inhibitor 3OG, which is among the most promising inhibitors in this class (23). We found that 1 M 3OG showed no inhibition of Cd 2+ influx through D580N mutant channels, while it inhibited nearly 70% of Cd 2+ influx through wild-type hTRPV6 channels ( fig.…”

Section: Functional Evaluation Of the Pchpd Pore Binding Sitementioning

confidence: 97%

“…Several small-molecule inhibitors of TRPV6, including 2-aminoethoxydiphenyl borate (2-APB; IC 50 = 71 M), have been identified, but the majority either are nonspecific or have low potency (17)(18)(19)(20)(21). In contrast, we developed the first small-molecule TRPV6 inhibitors, (4-phenylcyclohexyl)piperazine derivatives (PCHPDs), that are highly selective and have nanomolar affinity (21)(22)(23). Here, we solve x-ray and cryo-electron microscopy (cryo-EM) structures of TRPV6 in complex with several PCHPD inhibitors and identify PCHPD binding sites in the channel's TM domain.…”

Section: Introductionmentioning

confidence: 99%

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Inactivation-mimicking block of the epithelial calcium channel TRPV6

et al. 2020

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Epithelial calcium channel TRPV6 plays vital roles in calcium homeostasis, and its dysregulation is implicated in multifactorial diseases, including cancers. Here, we study the molecular mechanism of selective nanomolar-affinity TRPV6 inhibition by (4-phenylcyclohexyl)piperazine derivatives (PCHPDs). We use x-ray crystallography and cryo–electron microscopy to solve the inhibitor-bound structures of TRPV6 and identify two types of inhibitor binding sites in the transmembrane region: (i) modulatory sites between the S1-S4 and pore domains normally occupied by lipids and (ii) the main site in the ion channel pore. Our structural data combined with mutagenesis, functional and computational approaches suggest that PCHPDs plug the open pore of TRPV6 and convert the channel into a nonconducting state, mimicking the action of calmodulin, which causes inactivation of TRPV6 channels under physiological conditions. This mechanism of inhibition explains the high selectivity and potency of PCHPDs and opens up unexplored avenues for the design of future-generation biomimetic drugs.

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Section: Functional Evaluation Of the Pchpd Pore Binding Sitementioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Inactivation-mimicking block of the epithelial calcium channel TRPV6

et al. 2020

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“… [35] Some of these molecules have displayed biological activity. For example, penindolones were found to inhibit membrane fusion of the Influenza A virus, [42] and derivatives of piperazopyridones were identified as TRPV6 channel inhibitors [75] . Other applications include the preparation of pseudo‐NP dyes from betelamic acid [76] .…”

Section: Discussionmentioning

confidence: 99%

Pseudo Natural Products—Chemical Evolution of Natural Product Structure

et al. 2021

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Pseudo‐natural products (PNPs) combine natural product (NP) fragments in novel arrangements not accessible by current biosynthesis pathways. As such they can be regarded as non‐biogenic fusions of NP‐derived fragments. They inherit key biological characteristics of the guiding natural product, such as chemical and physiological properties, yet define small molecule chemotypes with unprecedented or unexpected bioactivity. We iterate the design principles underpinning PNP scaffolds and highlight their syntheses and biological investigations. We provide a cheminformatic analysis of PNP collections assessing their molecular properties and shape diversity. We propose and discuss how the iterative analysis of NP structure, design, synthesis, and biological evaluation of PNPs can be regarded as a human‐driven branch of the evolution of natural products, that is, a chemical evolution of natural product structure.

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“…Chow et al (2007) [ 209 ] suggested that 77 induces apoptosis preferentially via TRPV6, with selectivity for tumor cells. Recently, however, the activity of 77 against TRPV6 was evaluated in a Ca 2+ flux assay [ 134 , 210 ]. The authors observed that in this assay, the compound was not able to change the channel transport.…”

Section: Literature-related Cytotoxic Compoundsmentioning

confidence: 99%

“…In vivo mice models revealed that administration of 77 significantly reduced tumor growth (>50%) in breast and leukemia cancers [ 76 , 213 ]. As the inherent pungency of 77 greatly limits its application in therapeutics, it has led several research groups to design analogues lacking pungency of 77 [ 129 , 131 , 132 , 133 , 210 , 214 , 215 ].…”

Section: Literature-related Cytotoxic Compoundsmentioning

confidence: 99%

Peppers: A “Hot” Natural Source for Antitumor Compounds

et al. 2021

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Piper, Capsicum, and Pimenta are the main genera of peppers consumed worldwide. The traditional use of peppers by either ancient civilizations or modern societies has raised interest in their biological applications, including cytotoxic and antiproliferative effects. Cellular responses upon treatment with isolated pepper-derived compounds involve mechanisms of cell death, especially through proapoptotic stimuli in tumorigenic cells. In this review, we highlight naturally occurring secondary metabolites of peppers with cytotoxic effects on cancer cell lines. Available mechanisms of cell death, as well as the development of analogues, are also discussed.

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Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor

Abstract: Natural product derived analogues were surveyed, and an oxygenated analog was identified as a potent and selective TRPV6 inhibitor, with high microsomal stability and low off-target effects.

Cited by 24 publications

References 49 publications

Inactivation-mimicking block of the epithelial calcium channel TRPV6

Inactivation-mimicking block of the epithelial calcium channel TRPV6

Pseudo Natural Products—Chemical Evolution of Natural Product Structure

Peppers: A “Hot” Natural Source for Antitumor Compounds

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