PEGylation of a proprotein convertase peptide inhibitor for vaginal route of drug delivery: In vitro bioactivity, stability and in vivo pharmacokinetics

Ho, Henry Sun Sien; Nero, Tracy L.; Singh, Harmeet; Parker, Michael W.; Nie, Guiying

doi:10.1016/j.peptides.2012.09.014

Cited by 5 publications

(5 citation statements)

References 49 publications

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“…Our previous publication showed C-30k-PEG Poly R as a potent peptide-based PC6 inhibitor [9]. We thus compared these two different types of PC6 inhibitors compound 1o and C-30k-PEG Poly R, for their potency in inhibiting stromal cell decidualization and epithelial receptivity.…”

Section: Resultsmentioning

confidence: 99%

“…Data of C-30k-PEG Poly R was previously published in [9]. Each value represents mean ± SEM of three independent experiments.…”

Section: Resultsmentioning

confidence: 99%

“…An in vitro PC6 activity assay as described previously [8], [9] was used to evaluate PC6 inhibition by small molecule compounds. In brief, 2 units of active recombinant human PC6 (rhPC6) (PhenoSwitch BioScience Inc., Quebec, Canada) were incubated with small molecule compounds (10 µM), in Dulbecco's modified Eagle's medium/Ham's F12 culture medium (DMEM/F12, Sigma, St. Louis, MO) in the presence of 100 µM fluorogenic substrate pERTKR-AMC (Bachem, Torrance, CA) at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…The inhibition of decidualisation of primary HESCs by compound 1o was compared to that of a known peptide PC6 inhibitor, C-30k-PEG Poly R (synthesised by Mimotopes, Clayton, Australia), which was previously proved to potently inhibit decidualisation of primary HESCs [9]. The effect of C-30k-PEG Poly R on Ishikawa cell receptivity to trophoblast spheroids was also examined using the in vitro human trophoblast spheroid attachment assay as described above, and the results were compared to that of compound 1o.…”

Section: Methodsmentioning

confidence: 99%

“…To enable implantation, the uterus must acquire epithelial receptivity and undergo a process known as decidualization to differentiate stromal fibroblasts into phenotypically and functionally distinct decidual cells [5]. We have previously shown that PC6 is critical for both uterine epithelial receptivity and stromal cell decidualization [6], [7], [8], [9]. Knockdown of PC6 in a human endometrial epithelial cell line HEC1A significantly reduced its receptivity for blastocyst adhesion [6].…”

Section: Introductionmentioning

confidence: 99%

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Small Molecule Proprotein Convertase Inhibitors for Inhibition of Embryo Implantation

Singh²,

Heng

et al. 2013

PLoS ONE

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Uterine proprotein convertase (PC) 6 plays a critical role in embryo implantation and is pivotal for pregnancy establishment. Inhibition of PC6 may provide a novel approach for the development of non-hormonal and female-controlled contraceptives. We investigated a class of five synthetic non-peptidic small molecule compounds that were previously reported as potent inhibitors of furin, another PC member. We examined (i) the potency of these compounds in inhibiting PC6 activity in vitro; (ii) their binding modes in the PC6 active site in silico; (iii) their efficacy in inhibiting PC6-dependent cellular processes essential for embryo implantation using human cell-based models. All five compounds showed potent inhibition of PC6 activity in vitro, and in silico docking demonstrated that these inhibitors could adopt a similar binding mode in the PC6 active site. However, when these compounds were tested for their inhibition of decidualization of primary human endometrial stromal cells, a PC6-dependent cellular process critical for embryo implantation, only one (compound 1o) showed potent inhibition. The lack of activity in the cell-based assay may reflect the inability of the compounds to penetrate the cell membrane. Because compound's lipophilicity is linked to cell penetration, a measurement of lipophilicity (logP) was calculated for each compound. Compound 1o is unique as it appears the most lipophilic among the five compounds. Compound 1o also inhibited another crucial PC6-dependent process, the attachment of human trophoblast spheroids to endometrial epithelial cells (a model for human embryo attachment). We thus identified compound 1o as a potent small molecule PC6 inhibitor with pharmaceutical potential to inhibit embryo implantation. Our findings also highlight that human cell-based functional models are vital to complement the biochemical and in silico analyses in the selection of promising drug candidates. Further investigations for compound 1o are warranted in animal models to test its utility as an implantation-inhibiting contraceptive drug.

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Section: Resultsmentioning

confidence: 99%

“…Data of C-30k-PEG Poly R was previously published in [9]. Each value represents mean ± SEM of three independent experiments.…”

Section: Resultsmentioning

confidence: 99%