Molecular Dynamics Simulations Help Determine the Molecular Mechanisms of Lasioglossin-III and Its Variant Peptides’ Membrane Interfacial Interactions

Article

作者: Mylonakis, Eleftherios ; Mishra, Biswajit ; Basu, Anindya ; Kumar, Atul ; Konar, Anita Dutt

Lasioglossin-III (LL-III) is a potent broad-spectrum antimicrobial peptide used in diverse antimicrobial applications. In this work, coarse-grained and all-atom molecular dynamics simulation strategies were used in tandem to interpret the molecular mechanisms involved in the interfacial dynamics of LL-III and its recombinant variants during interactions with diverse cell membrane systems. Our results indicate that the membrane charges act as the driving force for initiating the membrane-peptide interactions, while the hydrophobic or van der Waals forces help to reinforce the membrane-peptide bindings. The optimized charge-hydrophobicity ratio of the LL-III peptides helps ensure their high specificity toward bacterial membranes compared to mammalian membrane systems, which also helps explain our experimental observations. Overall, we hope that our work gives new insight into the antimicrobial action of LL-III peptides and that the adopted simulation strategy will help other scientists and engineers extract maximal information from complex molecular simulations using minimal computational power.

2014-07-01·Nanomedicine: Nanotechnology, Biology and Medicine

Assessment of the antigen-specific antibody response induced by mucosal administration of a GnRH conjugate entrapped in lipid nanoparticles

Article

作者: Ferro, Valerie A ; Gebril, Ayman M ; Mullen, Alexander B ; Lamprou, Dimitrios A ; Alsaadi, Manal M ; Stimson, William H

Vaccines administered parenterally have been developed against gonadotrophin-releasing hormone (GnRH) for anti-fertility and anti-cancer purposes. The aim of this study was to demonstrate whether mucosal delivery using GnRH immunogens entrapped in lipid nanoparticles (LNP) could induce anti-GnRH antibody titers. Immunogens consisting of KLH (keyhole limpet hemocyanin) conjugated to either GnRH-I or GnRH-III analogues were entrapped in LNP. Loaded non-ionic surfactant vesicles (NISVs) were administered subcutaneously, while nasal delivery was achieved using NISV in xanthan gum and oral delivery using NISV containing deoxycholate (bilosomes). NISV and bilosomes had similar properties: they were spherical, in the nanometre size range, with a slightly negative zeta potential and surface properties that changed with protein loading and inclusion of xanthan gum. Following immunization in female BALB/c mice, systemic antibody responses were similar for both GnRH-I and GnRH-III immunization. Only nasal delivery proved to be successful in terms of producing systemic and mucosal antibodies.FROM THE CLINICAL EDITORThe main research question addressed in this study was whether mucosal delivery using gonadotrophin-releasing hormone immunogens entrapped in lipid nanoparticles could induce anti-GnRH antibody titers. Only nasal delivery proved to be successful in terms of producing systemic and mucosal antibodies with this approach.

2011-09-01·Journal of Cellular Biochemistry3区 · 生物学

Ubiquitination and downregulation of ErbB2 and estrogen receptor‐alpha by kinase inhibitor MP‐412 in human breast cancer cells

3区 · 生物学

Article

作者: Hiroshi Ochi ; Tsuyoshi Suzuki ; Hideo Nakamura ; Akihiro Fujii

AbstractErbB2 has been proven to be an important target for breast cancer therapy. MP‐412 is a dual ErbB2 and epidermal growth factor receptor tyrosine kinase inhibitor belonging to an irreversible‐type anilinoquinazoline derivative. We demonstrate herein that along with the kinase inhibition, MP‐412 has the ability to induce ubiquitination, internalization, and degradation of ErbB2 in several human breast cancer cell lines at concentrations relatively higher than those required for kinase inhibition. Another irreversible inhibitor, CI‐1033, showed similar activity, while the reversible compounds were ineffective, suggesting a crucial role of covalent bonding functionality in these effects. In MCF7 cells, MP‐412 depleted not only ErbB2 but also estrogen receptor (ER)‐α, and to some extent, affected Raf‐1, while MP‐412 activated Hsp70 expression. Moreover, we observed that MP‐412 increased immunocomplexing of Hsp70 with ErbB2 and ER‐α, with simultaneous induction of ubiquitination of these client proteins. Furthermore, in combination with proteasome inhibitor, MP‐412 resulted in the noticeable accumulation of ErbB2 and ER‐α in the detergent insoluble fraction of cell lysates. These results suggest that MP‐412 acts as an inhibitor of Hsp90 function, whereas MP‐412 did not bind directly to ATP‐binding site of Hsp90, unlike geldanamycin. We also found that new protein synthesis was involved in the activity of MP‐412 on Hsp90 modulation. Since downregulation of ErbB2 and ER‐α by accelerating the ubiquitin‐proteolysis system will become an attractive approach for breast cancer therapy, we expect MP‐412 to be a lead compound for the drug design and the development of such agents. J. Cell. Biochem. 112: 2279–2286, 2011. © 2011 Wiley‐Liss, Inc.

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