The proprotein convertases are a Niraparib in vivo family of nine serine proteases implicated in the processing of a multitude of precursor proteins. The first seven members activate a large number of polypeptide hormones, growth factors, adhesion molecules, various viral surface proteins and protoxins of bacteria by cleavage at basic residues. The eighth and ninth members do not require a basic residue for cleavage and they play major roles in regulation of lipid homeostasis. Accumulated evidence over the last decade has confirmed PCs as potential therapeutic targets for several important pathologies including osteoarthritis, cancer, cardiovascular disease and viral infections. Therefore, development of PC MLN4924 inhibitors is clearly an important research and development field. Our interest in PC inhibitors originated from studies aiming at inhibiting PC6 in the female reproductive tract to inhibit embryo implantation. Uterine PC6 is pivotal in embryo implantation and is essential for the establishment of pregnancy. 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. We have previously shown that PC6 is critical for both uterine epithelial receptivity and stromal cell decidualization. Knockdown of PC6 in a human endometrial epithelial cell line HEC1A significantly reduced its receptivity for blastocyst adhesion. Decidualization of primary human endometrial stromal cells was inhibited when PC6 activity was blocked. It has also been demonstrated in mice that when uterine PC6 production was blocked, decidualization was inhibited and implantation was prevented. In addition, PCs including PC6 also play an important role in HIV infection. Therefore, inhibition of PC6 is an attractive approach to develop novel, non-hormonal and female-controlled contraceptives that could also protect women from HIV infection. The majority of PC inhibitors reported in the literature to date have been proteins or peptides. Nona-D-arginine is one of the most potent peptide based PC inhibitors known to date. Poly R inhibits PC6 in vitro with a Ki in the nanomolar range and has been shown to inhibit HIV in cell culture. We have previously demonstrated that Poly R inhibits decidualization of HESC in culture and have evaluated the therapeutic potential of a PEGylated Poly R in inhibition of implantation in rabbits. However, the physiochemical properties of Poly R could limit their usefulness in therapeutic applications in women. Therefore, we continue to search for potent PC6 inhibitors with the desired characteristics such as serum stability and cell permeability. In this study, we evaluated five synthetic small molecule compounds derived from 2,5-dideoxystreptamine chemical scaffold previously reported by Jiao et al., 2006. Four of these compounds were previously shown to be potent inhibitors of both human furin and PC6 in vitro. Compound 1o was shown to be a relatively poor inhibitor of furin but no data on PC6 was reported. Here, the inhibitory potency of all five compounds against human PC6 was determined in vitro. In silico docking studies were performed to visualise the potential binding mode of these inhibitors in the active site of hPC6 and to gain an understanding of how this may relate to their inhibitory activity. The therapeutic potential of these small molecule inhibitors was then examined in in vitro human cell-based models to investigate their ability to inhibit two important PC6-mediated cellular processes essential for embryo implantation: decidualization of primary HESCs and attachment of human trophoblast spheroids to endometrial epithelial cells. PC6 plays a crucial role in embryo implantation and HIV infection; it is therefore highly desirable to develop inhibitors of PC6 for potential non-hormonal female contraceptives that could also protect women from HIV. In the ongoing search for PC6 inhibitors with appropriate physiochemical characteristics for therapeutic applications, we investigated five synthetic small molecule compounds that had been previously reported as inhibitors of furin, another PC member. Our studies revealed that all five compounds were potent inhibitors against rhPC6 in vitro and they were able to adopt similar binding modes in the hPC6 active site. However, the functional studies by in vitro cell-based model demonstrated that only compound 1o was able to inhibit decidualization of HESCs.