Zanamivir Amidoxime- and N-Hydroxyguanidine-Based Prodrug Approaches to Tackle Poor Oral Bioavailability

Schade, Dennis; Kotthaus, Jürke; Riebling, Lukas; Kotthaus, Joscha; Müller-Fielitz, Helge; Raasch, Walter; Hoffmann, Anja; Schmidtke, Michaela; Clement, Bernd

doi:10.1002/jps.24508

Cited by 23 publications

(33 citation statements)

References 40 publications

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“…The readout of the FL assay is based on the quantification of the FL signal released after cleavage of the sialic acid-containing synthetic substrate (MUNANA) by NAs of the H1N1 influenza virus strains A/WSN/1933 (WSN/3325) and A/Jena/8178/2009 (8178/09; A(H1N1)pdm09 strain), and the recombinant NanA of pneumococcal strain DSM20566 (rNanA) at pH 6.013. In order to rule out false positive or negative results, all samples were checked for FL quenching and self-FL as described previously (Supplementary Table S1)13.…”

Section: Resultsmentioning

confidence: 99%

“…H1N1 influenza virus WSN/33 (amantadin-sensitive25) and A/Jena/8178/2009 (8178/09) were applied in the fluorescence (FL)-based neuraminidase (NA) inhibition (FL assay) as well as in the cytopathic effect (CPE) inhibition assay. Strain 8178/09 was additionally used to study the inhibitory effect of neuraminidase inhibitors (NAIs) in the presence and absence of bacterial neuraminidase (NA) in A549 cells.…”

Section: Methodsmentioning

confidence: 99%

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Discovery of prenylated flavonoids with dual activity against influenza virus and Streptococcus pneumoniae

Grienke

Richter

Walther

et al. 2016

Sci Rep

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Influenza virus neuraminidase (NA) is the primary target for influenza therapeutics. Severe complications are often related to secondary pneumonia caused by Streptococcus pneumoniae (pneumococci), which also express NAs. Recently, a NA-mediated lethal synergism between influenza A viruses and pneumococci was described. Therefore, dual inhibitors of both viral and bacterial NAs are expected to be advantageous for the treatment of influenza. We investigated the traditional Chinese herbal drug sāng bái pí (mulberry root bark) as source for anti-infectives. Two prenylated flavonoid derivatives, sanggenon G (4) and sanggenol A (5) inhibited influenza A viral and pneumococcal NAs and, in contrast to the approved NA inhibitor oseltamivir, also planktonic growth and biofilm formation of pneumococci. Evaluation of 27 congeners of 5 revealed a correlation between the degree of prenylation and bioactivity. Abyssinone-V 4′-methyl ether (27) inhibited pneumococcal NA with IC50 = 2.18 μM, pneumococcal growth with MIC = 5.63 μM, and biofilm formation with MBIC = 4.21 μM, without harming lung epithelial cells. Compounds 5 and 27 also disrupt the synergism between influenza A virus and pneumococcal NA in vitro, hence functioning as dual-acting anti-infectives. The results warrant further studies on whether the observed disruption of this synergism is transferable to in vivo systems.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Discovery of prenylated flavonoids with dual activity against influenza virus and Streptococcus pneumoniae

Grienke

Richter

Walther

et al. 2016

Sci Rep

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“…The synthesis of pleconaril and its purity (99.9 %) were described previously [42]. The drug zanamivir (GlaxoSmithKline) was used as the reference compound in the anti-influenza virus assay [43]. Stock solutions of pleconaril and zanamivir (10 000 µM) were prepared in dimethyl sulfoxide and bidistilled water, respectively.…”

Section: Control Compoundsmentioning

confidence: 99%

High-performance Countercurrent Chromatography to Access Rhodiola rosea Influenza Virus Inhibiting Constituents

et al. 2020

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In a cytopathic effect inhibition assay, a standardized Rhodiola rosea root and rhizome extract, also known as roseroot extract (SHR-5), exerted distinct anti-influenza A virus activity against HK/68 (H3N2) (IC50 of 2.8 µg/mL) without being cytotoxic. For fast and efficient isolation and identification of the extractʼs bioactive constituents, a high-performance countercurrent chromatographic separation method was developed. It resulted in a three-stage gradient elution program using a mobile phase solvent system composed of ethyl acetate/n-butanol/water (1 : 4 : 5 → 2 : 3 : 5 → 3 : 2 : 5) in the reversed-phase mode. The elaborated high-performance countercurrent chromatographic method allowed for fractionation of the complex roseroot extract in a single chromatographic step in a way that only one additional orthogonal isolation/purification step per fraction yielded 12 isolated constituents. They cover a broad polarity range and belong to different structural classes, namely, the phenylethanoid tyrosol and its glucoside salidroside, the cinnamyl alcohol glycosides rosavin, rosarin, and rosin as well as gallic acid, the cyanogenic glucoside lotaustralin, the monoterpene glucosides rosiridin and kenposide A, and the flavonoids tricin, tricin-5-O-β-D-glucopyranoside, and rhodiosin. The most promising anti-influenza activities were determined for rhodiosin, tricin, and tricin-5-O-β-D-glucopyranoside with IC50 values of 7.9, 13, and 15 µM, respectively. The herein established high-performance countercurrent chromatographic protocol enables fast and scalable access to major as well as minor roseroot constituents. This is of particular relevance for extract standardization, quality control, and further in-depth pharmacological investigations of the metabolites of this popular traditional herbal remedy.

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“…13 On the other hand, resistance to the other three neuraminidase inhibitors (zanamivir, laninamivir and peramivir) have been rarely reported, however they are very poorly absorbed after oral administration. The low absorption is likely due to the highly polar and positively charged guanidino functionality 14, 15 which importantly appears to make a significant contribution to the neuraminidase inhibition potency. Compared to the amino group in oseltamivir carboxylate, the guanidino functionality adds more hydrophilic character to the molecule making it less likely to be absorbed after oral administration.…”

Section: Introductionmentioning

confidence: 99%

“…18, 19 On the contrary, it has been recently demonstrated that the prodrug strategies based on the bioisosteric replacement of the guanidino group by an acetamidine (zanamivir amidoxime) and lowering the basicity of the guanidino and its bioisosteric amidine by N-hydroxylation fail to improve the oral bioavailability of zanamavir (F ≤ 3.7). 15 …”

Section: Introductionmentioning

confidence: 99%

Carrier-Mediated Prodrug Uptake to Improve the Oral Bioavailability of Polar Drugs: An Application to an Oseltamivir Analogue

Incecayir

Sun

Tsume

et al. 2016

Journal of Pharmaceutical Sciences

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The goal of this study was to improve the intestinal mucosal cell membrane permeability of the poorly absorbed guanidino analogue of a neuraminidase inhibitor, oseltamivir carboxylate (GOC) using a carrier mediated strategy. Valyl amino acid prodrug of GOC with isopropylmethylenedioxy linker (GOC-ISP-Val) was evaluated as the potential substrate for intestinal oligopeptide transporter, hPEPT1 in Xenopus laevis oocytes heterologously expressing hPEPT1and an intestinal mouse perfusion system. The diastereomers of GOC-ISP-Val were assessed for chemical and metabolic stability. Permeability of GOC-ISP-Val was determined in Caco-2 cells and mice. Diastereomer 2 was about two times more stable than diastereomer 1 in simulated intestinal fluid and rapidly hydrolyzed to the parent drug in cell homogenates. The prodrug had a nine times enhanced apparent permeability (P app ) in Caco-2 cells compared to the parent drug. Both diastereomer exhibited high effective permeability (P eff ) in mice, 6.32±3.12 and 5.20±2.81 x10 −5 cm/s for diastereomer 1 and 2, respectively. GOC-ISP-Val was found to be a substrate of hPEPT1. Overall, this study indicates that the prodrug, GOC-ISP-Val seems to be a promising oral anti-influenza agent that has sufficient stability at physiologically relevant pHs prior to absorption, significantly improved permeability via hPEPT1 and potentially rapid activation in the intestinal cells.

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Zanamivir Amidoxime- and N-Hydroxyguanidine-Based Prodrug Approaches to Tackle Poor Oral Bioavailability

Cited by 23 publications

References 40 publications

Discovery of prenylated flavonoids with dual activity against influenza virus and Streptococcus pneumoniae

Discovery of prenylated flavonoids with dual activity against influenza virus and Streptococcus pneumoniae

High-performance Countercurrent Chromatography to Access Rhodiola rosea Influenza Virus Inhibiting Constituents

Carrier-Mediated Prodrug Uptake to Improve the Oral Bioavailability of Polar Drugs: An Application to an Oseltamivir Analogue

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