Search

Antimicrobial peptides (AMPs) are regarded as host defense peptides that possess bactericidal activity as well as immunomodulatory function. However, the role of AMP in the mammalian ovary is unknown. In the present study, porcine granulosa cells were utilized in a cell model to study the role of porcine beta defensin 2 (pBD2; pDEFB4B) and 3 (pBD3; pDEFB103A) during ovarian follicular development. Granulosa cells were cultured in the absence and presence of 1, 10, and 50 μg/ml of pDEFB4B or pDEFB103A. After 24 h of treatment, pDEFB103A but not pDEFB4B stimulated granulosa cell proliferation in a concentration-dependent manner (P < 0.05). This effect was dependent on the stage of follicular development. In addition, transwell cell migration assay showed that in the presence of pDEFB103A (10 μg/ml), a 2.5-fold increase in cell migration was achieved. Furthermore, further study revealed that pDEFB103A increased the mRNA levels of cyclin D1 (CCND1) and proliferating cell nuclear antigen (PCNA), both associated with cell proliferation. To study the potential pathway involved in pDEFB103A-induced cell proliferation and migration, western blots were performed. It was found that pDEFB103A significantly increased the phosphorylated-ERK1/2 to nonphosphorylated ratio. Moreover, pretreatment with the U0126, a specific ERK1/2 phosphorylation inhibitor, suppressed PDEFB103A inducing GCs ERK1/2 phosphorylation, as well as proliferation and migration, suggesting that PDEFB103A may act via activating the ERK1/2 pathway. Furthermore, using a signal transduction pathway Elk-1 trans-reporting system, the activation of ERK1/2 pathway by PDEFB103A was further confirmed. Our data suggest that AMP may play a physiological role in the mammalian ovary.

Background: The GlcNAc related sulfated disaccharides were reported to show inhibitory activity on breast tumor cells (MDA-MB-231). However, synthesis of sulfated disaccharides is laborious and time consuming, and there is a need to find more efficient methods to generate the sulfated disaccharide libraries in acceptable ratios and in respectable yields. Random glycosylation followed by sulfation may be a good method to synthesize sulfated disaccharide library. However, there is a dearth of simple methods to generate the GalNAc and GlcNAc related disaccharides with acceptable ratio by random glycosylation. Results: Following a generic procedure, random glycosylation of unprotected monosaccharides and followed by deprotection, acetylation, deacetylation, and purification, yielded the GalNAc-GlcNAc disaccharide library containing three β-linked disaccharides with a 1:1:1 ratio and the GlcNAc-Gal disaccharide library containing four β-linked disaccharides with 1:1:2:2 ratio. These results were confirmed by comparison of their proton NMR spectra with that of standard disaccharides. Conclusion: Random glycosylation was employed to generate GalNAc and GlcNAc related disaccharide libraries and was demonstrated as the most efficient method thus far for the synthesis of GalNAc and GlcNAc related disaccharide libraries with excellent ratios, which further can be used as the starting materials for random sulfation to synthesize the sulfated disaccharide libraries.

Background: HIV-1 protease is a prime target for drug therapy due to its integral role in HIV viral replication. Several protease inhibitors such as lopinavir and tipranavir were shown to possess potent inhibitory activities against the HIV virus. Due to the high mutation rate of HIV, resistance remains a major problem in the treatment of this virus and design and synthesis of new protease inhibitors is an area of continued interest in new drug discovery research. Methods: Utilizing the key fragments of structures of both peptide-based and non-peptide-based protease inhibitors lopinavir and tipranavir, we explored designing some new compounds. Results: Six new protease inhibitors were designed and synthesized based on the key structural fragments in lopinavir and tipranavir. The designed new compounds contain heterocyclic groups such as thiophene, isoxazole, and imidazole groups, and the best compound exhibited 0.6 nm of the protease inhibitory activity. Conclusion: We have prepared some novel heterocyclic sulfonamides utilizing a key fragment based approach by recombining structural fragments of the potent protease inhibitors lopinavir and tipranavir. Some of these newly designed compounds showed good to excellent HIV-1 protease inhibitory activity, which indicated that this method would be useful for the discovery of new drug lead compounds that target HIV.

Background: The biological significance of glycoconjugates has stimulated much synthetic activity in oligosaccharide synthesis, the sulfate group in sulfated oligosaccharides has been shown to be constitutively involved in the interaction of ligands with selectins, establishing combinatorial methods for the synthesis of sulfated oligosaccharide library may be useful for screening of ligands of selectins. Results: Random sulfation of a partial benzyl protected Lewis A trisaccharide in pyridine provided a sulfated trisaccharide mixture. After hydrogenation with Pd/C and purification on Sephadex A-50 column, a monosulfated trisaccharide library was obtained as a mixture. The H-H COSY NMR spectrum of this mixture showed that this mixture contains all five possible monosulfated Lewis A trisaccharides with acceptable ratio. Conclusion: Random sulfation of a partial protected oligosaccharide was demonstrated as the most efficient method so far for the synthesis of monosulfated oligosaccharide library.

Starting from an unprotected GlcNAc acceptor, after first random glycosylation and deprotection, and second random glycosylation, deprotection, and purification, we were able to obtain a trisaccharide library containing 36 α-linked trisaccharide library. These compounds were characterized by 1D, 2D NMR and mass spectra. The library was used as the starting material for enzymatic reaction to obtain a tetrasaccharide in support of the results. Based on this method, a trisaccharide library containing 15 α-linked trisaccharides was synthesized.

Fondaparinux (trade name Arixtra) is a safe and efficacious anticoagulant, and it is chemically related to low-molecular-weight heparins such as enoxaparin. Fondaparinux is a synthetic pentasaccharide, and its synthesis is difficult and expensive. The high cost of fondaparinux thwarts its extensive worldwide usage. Over the last two decades, several research groups and pharmaceutical companies have been interested in finding efficient and practical methods for its synthesis. The present review discusses those strategies and their pros and cons in a comparative account.