Library-Based Discovery and Characterization of Daphnane Diterpenes as Potent and Selective HIV Inhibitors in <i>Daphne gnidium</i>

Vidal, Vincent; Potterat, Olivier; Louvel, Séverine; Hamy, François; Mojarrab, Mahdi; Sanglier, Jean‐Jacques; Klimkait, Thomas; Hamburger, Matthias

doi:10.1021/np200855d

Cited by 53 publications

(36 citation statements)

References 31 publications

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“…29 More recently, DDOs have also been identified as potent and selective in vitro HIV inhibitors. 17 Although some DDOs possess interesting biological activities, Extraction. The air-dried roots (180 g) of G. polycephala were ground into a powder and percolated with DCM (3 × 700 mL, 24 h each) at room temperature.…”

Section: Journal Of Natural Productsmentioning

confidence: 99%

hERG Channel Inhibitory Daphnane Diterpenoid Orthoesters and Polycephalones A and B with Unprecedented Skeletons from Gnidia polycephala

Mieri¹,

Du²,

Neuburger³

et al. 2015

J. Nat. Prod.

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The hERG channel is an important antitarget in safety pharmacology. Several drugs have been withdrawn from the market or received severe usage restrictions because of hERG-related cardiotoxicity. In a screening of medicinal plants for hERG channel inhibition using a two-microelectrode voltage clamp assay with Xenopus laevis oocytes, a dichloromethane extract of the roots of Gnidia polycephala reduced the peak tail hERG current by 58.8 ± 13.4% (n = 3) at a concentration of 100 μg/mL. By means of HPLC-based activity profiling daphnane-type diterpenoid orthoesters (DDOs) 1, 4, and 5 were identified as the active compounds [55.4 ± 7.0% (n = 4), 42.5 ± 16.0% (n = 3), and 51.3 ± 9.4% (n = 4), respectively, at 100 μM]. In a detailed phytochemical profiling of the active extract, 16 compounds were isolated and characterized, including two 2-phenylpyranones (15 and 16) with an unprecedented tetrahydro-4H-5,8-epoxypyrano[2,3-d]oxepin-4-one skeleton, two new DDOs (3 and 4), two new guaiane sesquiterpenoids (11 and 12), and 10 known compounds (1, 2, 5-10, 13, and 14). Structure elucidation was achieved by extensive spectroscopic analysis (1D and 2D NMR, HRMS, and electronic circular dichroism), computational methods, and X-ray crystallography.

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Section: Journal Of Natural Productsmentioning

confidence: 99%

hERG Channel Inhibitory Daphnane Diterpenoid Orthoesters and Polycephalones A and B with Unprecedented Skeletons from Gnidia polycephala

Mieri¹,

Du²,

Neuburger³

et al. 2015

J. Nat. Prod.

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“…Selectivity indices for P. falciparum were 0.1 to 18.2, and 0.1 to 1.2 for T. brucei rhodesiense. ceptor modulators, and anti-HIV compounds [12][13][14][15][16][17][18][19]. Continuing in our screening of medicinal plants for the discovery of new antiparasitic natural products with scaffolds new for the target, we recently screened over 150 plant extracts mainly from the Labiatae and Asteraceae families from the Iranian flora.…”

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confidence: 99%

Abietane Diterpenoids from Salvia sahendica – Antiprotozoal Activity and Determination of Their Absolute Configurations

et al. 2013

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In a screening of Iranian plants for antiprotozoal activity, an n-hexane extract of the roots of Salvia sahendica potently inhibited the growth of Plasmodium falciparum K1 strain. Subsequent HPLC-based activity profiling led to the identification of seven known and one new abietane-type diterpenoid. Structure elucidation was achieved by analysis of spectroscopic data including 1D and 2D NMR. The absolute configuration of sahandol (7) and sahandone (8) were assigned by comparison of experimental ECD spectra with calculated ECD data, using time-dependent density functional theory and methanol as the solvent. In vitro biological activity against P. falciparum and Trypanosoma brucei rhodesiense STIB 900 strain and cytotoxicity in rat myoblast (L6) cells were determined. The IC50 values of the compounds ranged from 0.8 µM to over 8.8 µM against P. falciparum, and from 1.8 µM to over 32.3 µM against T. brucei rhodesiense. The cytotoxic IC50 values ranged from 0.5-15.5 µM. Selectivity indices for P. falciparum were 0.1 to 18.2, and 0.1 to 1.2 for T. brucei rhodesiense.

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“…Principles and details of the replicative phenotyping protocol have been described elsewhere (27,28) with the following adaptations for tropism analysis. Amplification of the HIV-1 Env gene isolated from clinical samples was successfully performed when virus loads were greater than 500 copies/ml (29).…”

Section: Methodsmentioning

confidence: 99%

A Diagnostic HIV-1 Tropism System Based on Sequence Relatedness

et al. 2015

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dKey clinical studies for HIV coreceptor antagonists have used the phenotyping-based Trofile test. Meanwhile various simplerto-do genotypic tests have become available that are compatible with standard laboratory equipment and Web-based interpretation tools. However, these systems typically analyze only the most prominent virus sequence in a specimen. We present a new diagnostic HIV tropism test not needing DNA sequencing. The system, XTrack, uses physical properties of DNA duplexes after hybridization of single-stranded HIV-1 env V3 loop probes to the clinical specimen. Resulting "heteroduplexes" possess unique properties driven by sequence relatedness to the reference and resulting in a discrete electrophoretic mobility. A detailed optimization process identified diagnostic probe candidates relating best to a large number of HIV-1 sequences with known tropism. From over 500 V3 sequences representing all main HIV-1 subtypes (Los Alamos database), we obtained a small set of probes to determine the tropism in clinical samples. We found a high concordance with the commercial TrofileES test (84.9%) and the Web-based tool Geno2Pheno (83.0%). Moreover, the new system reveals mixed virus populations, and it was successful on specimens with low virus loads or on provirus from leukocytes. A replicative phenotyping system was used for validation. Our data show that the XTrack test is favorably suitable for routine diagnostics. It detects and dissects mixed virus populations and viral minorities; samples with viral loads (VL) of <200 copies/ml are successfully analyzed. We further expect that the principles of the platform can be adapted also to other sequence-divergent pathogens, such as hepatitis B and C viruses. The predominant virus variant in early stages of the clinical manifestation of disease, CCR5-tropic HIV, is found in approximately 80% of treatment-naive patients (1, 2). Although this number can vary for the different virus subtypes, the percentage of CXCR4-tropic HIV isolates is generally low and tends to rise with disease progression (3-6). Nevertheless, the fraction of CCR5-tropic viruses in clinical specimens continues to stay at Ͼ50% throughout the course of infection (7,8). As such, the molecular interactions between the viral envelope and the cellular chemokine receptor CCR5 were recognized as potentially attractive targets for drug development and have yielded compounds and drugs able to specifically block CCR5-tropic HIV (9-11). It is this selectivity of the inhibition of one (CCR5) and not the other (CXCR4) viral coreceptor that necessitates tropism testing prior to prescribing drugs of this particular class. Although the chemokine receptor binding site in the HIV envelope is constituted mainly by the V3 loop, the V1/V2 regions, and the C4 conserved region in the HIV protein gp120, coreceptor tropism is dictated predominantly by amino acid sequences of the V3 region (12, 13). But also sequences of other variable env regions can contribute as secondary sites to the viral tropism (14-17).Initially, all...

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Library-Based Discovery and Characterization of Daphnane Diterpenes as Potent and Selective HIV Inhibitors in Daphne gnidium

Cited by 53 publications

References 31 publications

hERG Channel Inhibitory Daphnane Diterpenoid Orthoesters and Polycephalones A and B with Unprecedented Skeletons from Gnidia polycephala

hERG Channel Inhibitory Daphnane Diterpenoid Orthoesters and Polycephalones A and B with Unprecedented Skeletons from Gnidia polycephala

Abietane Diterpenoids from Salvia sahendica – Antiprotozoal Activity and Determination of Their Absolute Configurations

A Diagnostic HIV-1 Tropism System Based on Sequence Relatedness

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