Using the MCoTI-II Cyclotide Scaffold To Design a Stable Cyclic Peptide Antagonist of SET, a Protein Overexpressed in Human Cancer.

The SET protein is a promising drug target in cancer therapy, because of its ability to inhibit the function of the tumor suppressor gene protein phosphatase 2A (PP2A). COG peptides, derived from apolipoprotein E (apoE), are potent antagonists of SET; they induce cytotoxicity in cancer cells upon binding to intracellular SET and modulate the nuclear factor kappa B (NF-κB) signaling pathway. However, the therapeutic potential of COG peptides is limited, because of their poor proteolytic stability and low bioavailability. In this study, the COG peptide, COG1410, was stabilized by grafting it onto the ultrastable cyclic peptide scaffold, Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II). The grafted MCoTI-II peptides were cytotoxic to a cancer cell line and showed high stability in human serum. The most potent grafted MCoTI-II peptide inhibited lipopolysaccharide (LPS)-mediated activation of NF-κB in murine macrophages. Overall, this study demonstrates the application of the MCoTI-II scaffold for the development of stable peptide drugs for cancer therapy.

The association of noise and surgical-site infection in day-case hernia repairs.

INTRODUCTION: Surgical-site infections (SSIs) are associated with an increased duration of hospital stay, poorer quality of life, and an marked increase in cost to the hospital. Lapses in compliance with aseptic principles are a substantial risk factor for SSI, which may be attributable to distractions such as noise during the operation. The aims of this study were to assess whether noise levels in the operating room are associated with the development of SSI and to elucidate the extent to which these levels affect the financial burden of surgery. METHODS: Prospective data collection from elective, day-case male patients undergoing elective hernia repairs was undertaken. Patients were included if they were fit and at low risk for SSI. Sound levels during procedures was measured via a decibel meter and correlated with the incidence of SSI. Data analysis was performed with IBM SPSS (IBM, Armonk, NY). RESULTS: Noise levels were substantially greater in patients with SSI from time point of 50 minutes onwards, which correlated to when wound closure was occurring. Additional hospital costs for these patients were £243 per patient based on the National Health Service 2013 reference costing. CONCLUSION: Decreasing ambient noise levels in the operating room may aid in reducing the incidence of SSIs, particularly during closure, and decrease the associated financial costs of this complication.

Structural parameters modulating the cellular uptake of disulfide-rich cyclic cell-penetrating peptides: MCoTI-II and SFTI-1.

Peptides are emerging as a new class of therapeutics due to their high potency and specificity for a range of targets, including the inhibition of protein-protein interactions. Disulfide-rich cyclic peptides, in particular, have attracted much attention in drug design due to their ultra-stable structure. Moreover, some of them have been shown to internalize into cells, which makes them potential scaffolds to deliver pharmaceutically bioactive sequences to intracellular targets. Here we examined the effects of structural modifications on the cell-penetrating properties of two disulfide-rich cyclic cell-penetrating peptides, Momordica cochinchinensis trypsin inhibitor II (MCoTI-II) and sunflower trypsin inhibitor-1 (SFTI-1). We found that the cellular uptake of MCoTI-II can be improved by increasing the overall positive charge of the native sequence. On the other hand, mutations to SFTI-1 did not significantly influence its cellular uptake, suggesting a non-specific endocytosis-dependent mechanism of cellular uptake. This study provides an understanding of the structural features affecting the internalization of MCoTI-II and SFTI-1, and hence provides a guide for the development of these disulfide-rich cyclic scaffolds into potential drug leads.

Rational development of neuraminidase inhibitor as novel anti-flu drug.

The highly pathogenic influenza virus has caused many human fatalities and poses an increasing pandemic threat. Neuraminidase inhibitors such as oseltamivir and zanamivir have been widely used in the treatment and have gained remarkable success. Although, they are effective in prevention of influenza; the concern for drug resistance still remains a question. Recently, the availability of crystal structures of the enzyme gave a new trend to the structure based drug designing of neuraminidase inhibitors. The article reviews a detailed understanding of the structural features within neuraminidase enzyme which turnouts to be crucial for future drug development. In depth analysis for the newly proposed spots within the 150 and 430-loop regions in N1 makes it distinguishable among the subtypes. Further we have discussed the various computational studies carried out in optimizing the designing of neuraminidase inhibitors thereby providing new clues to modify the currently available drugs.

Search for novel neuraminidase inhibitors: Design, synthesis and interaction of oseltamivir derivatives with model membrane using docking, NMR and DSC methods.

As a part of our ongoing program of developing novel influenza virus inhibitors, some new derivatives of oseltamivir were prepared by modifying the amino group with glycyl, acetyl, benzyl and prolyl moieties. The interactions of these derivatives with neuraminidase have been probed by molecular modeling techniques. Further, the interaction of these derivatives with model membranes prepared from DPPC and the effect on the thermotropic behavior and polymorphism of the bilayers have been investigated by multinuclear NMR and DSC methods. Results indicate that the glycyl derivative of oseltamivir has the most profound effects on the membrane, compared to other derivatives and seems to be the most promising derivative for further pharmacological evaluation as a neuraminidase inhibitor.

Probing molecular level interaction of oseltamivir with H5N1-NA and model membranes by molecular docking, multinuclear NMR and DSC methods.

Structure-based drug design has led to the introduction of three drugs--oseltamivir (GS-4104), zanamivir (GG-167) and peramivir (RWJ-270201) which target the enzyme neuraminidase, for treatment of influenza infections. Using comparative docking studies we propose that more potent molecules against neuraminidase can be obtained by appending extra positively charged substituents at the C5 position of the oseltamivir skeleton. This provides an additional interaction with the enzyme and may overcome the problem of resistance encountered with these drugs. To get an insight into the transport and absorption of oseltamivir--the ethyl ester prodrug (GS-4104) as well as its mechanism of action, we have carried out 1H, 13C, 31P NMR, DSC and TEM studies on GS-4104 with model membranes prepared from DMPC/DPPC/POPC. These studies reveal that interactions between GS-4104 and the membrane are both electrostatic (involving H-bonding) and hydrophobic (involving the hydrophobic chain and cyclohexene ring of GS-4104) in nature. The prodrug is seen to increase the fluidity as well as stabilize the bilayer phase of the membrane. This property may be responsible for preventing viral entry into the cells by preventing fusion of the virus outer coat with the cell membrane.