Drug and Alcohol Rehabilitation: Bispidine-Amino Acid Conjugates Act as a Novel Scaffold for the Design of Antivirals That Block Japanese Encephalitis Virus Replication.

Bispidine-amino Acid conjugates act as a novel scaffold for the design of antivirals that block Japanese encephalitis virus replication.

Filed under: Drug and Alcohol Rehabilitation

PLoS Negl Trop Dis. 2013 Jan; 7(1): e2005
Haridas V, Rajgokul KS, Sadanandan S, Agrawal T, Sharvani V, Gopalakrishna MV, Bijesh MB, Kumawat KL, Basu A, Medigeshi GR

Japanese encephalitis virus (JEV) is a major cause of viral encephalitis in South and South-East Asia. Lack of antivirals and non-availability of affordable vaccines in these endemic areas are a major setback in combating JEV and other closely related viruses such as West Nile virus and dengue virus. Protein secondary structure mimetics are excellent candidates for inhibiting the protein-protein interactions and therefore serve as an attractive tool in drug development. We synthesized derivatives containing the backbone of naturally occurring lupin alkaloid, sparteine, which act as protein secondary structure mimetics and show that these compounds exhibit antiviral properties.In this study we have identified 3,7-diazabicyclo[3.3.1]nonane, commonly called bispidine, as a privileged scaffold to synthesize effective antiviral agents. We have synthesized derivatives of bispidine conjugated with amino acids and found that hydrophobic amino acid residues showed antiviral properties against JEV. We identified a tryptophan derivative, Bisp-W, which at 5 µM concentration inhibited JEV infection in neuroblastoma cells by more than 100-fold. Viral inhibition was at a stage post-entry and prior to viral protein translation possibly at viral RNA replication. We show that similar concentration of Bisp-W was capable of inhibiting viral infection of two other encephalitic viruses namely, West Nile virus and Chandipura virus.We have demonstrated that the amino-acid conjugates of 3,7-diazabicyclo[3.3.1]nonane can serve as a molecular scaffold for development of potent antivirals against encephalitic viruses. Our findings will provide a novel platform to develop effective inhibitors of JEV and perhaps other RNA viruses causing encephalitis.
HubMed – drug

A Comparison of Ku0063794, a Dual mTORC1 and mTORC2 Inhibitor, and Temsirolimus in Preclinical Renal Cell Carcinoma Models.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2013; 8(1): e54918
Zhang H, Berel D, Wang Y, Li P, Bhowmick NA, Figlin RA, Kim HL

Rapamycin analogs, temsirolimus and everolimus, are approved for the treatment of advance renal cell carcinoma (RCC). Currently approved agents inhibit mechanistic target of rapamycin (mTOR) complex 1 (mTORC1). However, the mTOR kinase exists in two distinct multiprotein complexes, mTORC1 and mTORC2, and both complexes may be critical regulators of cell metabolism, growth and proliferation. Furthermore, it has been proposed that drug resistance develops due to compensatory activation of mTORC2 signaling during treatment with temsirolimus or everolimus. We evaluated Ku0063794, which is a small molecule that inhibits both mTOR complexes. Ku0063794 was compared to temsirolimus in preclinical models for renal cell carcinoma. Ku0063794 was effective in inhibiting the phosphorylation of signaling proteins downstream of both mTORC1 and mTORC2, including p70 S6K, 4E-BP1 and Akt. Ku0063794 was more effective than temsirolimus in decreasing the viability and growth of RCC cell lines, Caki-1 and 786-O, in vitro by inducing cell cycle arrest and autophagy, but not apoptosis. However, in a xenograft model there was no difference in the inhibition of tumor growth by Ku0063794 or temsirolimus. A potential explanation is that temsirolimus has additional effects on the tumor microenvironment. Consistent with this possibility, temsirolimus, but not Ku0063794, decreased tumor angiogenesis in vivo, and decreased the viability of HUVEC (Human Umbilical Vein Endothelial Cells) cells in vitro at pharmacologically relevant concentrations. Furthermore, expression levels of VEGF and PDGF were lower in Caki-1 and 786-O cells treated with temsirolimus than cells treated with Ku0063794.
HubMed – drug

Controlled Release of Simvastatin from Biomimetic ?-TCP Drug Delivery System.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2013; 8(1): e54676
Chou J, Ito T, Bishop D, Otsuka M, Ben-Nissan B, Milthorpe B

Simvastatin have been shown to induce bone formation and there is currently a urgent need to develop an appropriate delivery system to sustain the release of the drug to increase therapeutic efficacy whilst reducing side effects. In this study, a novel drug delivery system for simvastatin by means of hydrothermally converting marine exoskeletons to biocompatible beta-tricalcium phosphate was investigated. Furthermore, the release of simvastatin was controlled by the addition of an outer apatite coating layer. The samples were characterized by x-ray diffraction analysis, fourier transform infrared spectroscopy, scanning electron microscopy and mass spectroscopy confirming the conversion process. The in-vitro dissolution of key chemical compositional elements and the release of simvastatin were measured in simulated body fluid solution showing controlled release with reduction of approximately 25% compared with un-coated samples. This study shows the potential applications of marine structures as a drug delivery system for simvastatin.
HubMed – drug

Mucuna pruriens and Its Major Constituent L-DOPA Recover Spermatogenic Loss by Combating ROS, Loss of Mitochondrial Membrane Potential and Apoptosis.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2013; 8(1): e54655
Singh AP, Sarkar S, Tripathi M, Rajender S

The Ayurvedic medicinal system claims Mucuna pruriens (MP) to possess pro-male fertility, aphrodisiac and adaptogenic properties. Some scientific evidence also supports its pro-male fertility properties; however, the mechanism of its action is not yet clear. The present study aimed at demonstrating spermatogenic restorative efficacy of MP and its major constituent L-DOPA (LD), and finding the possible mechanism of action thereof in a rat model.Ethinyl estradiol (EE) was administered at a rate of 3 mg/kg body weight (BW)/day for a period of 14 days to generate a rat model with compromised spermatogenesis. MP and LD were administered in two separate groups of these animals starting 15(th) day for a period of 56 days, and the results were compared with an auto-recovery (AR) group. Sperm count and motility, testis histo-architecture, level of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), apoptosis, peripheral hormone levels and testicular germ cell populations were analysed, in all experimental groups. We observed efficient and quick recovery of spermatogenesis in MP and LD groups in comparison to the auto-recovery group. The treatment regulated ROS level, apoptosis, and mitochondrial membrane potential (MMP), recovered the hypothalamic-pituitary-gonadal axis and the number of testicular germ cells, ultimately leading to increased sperm count and motility.M. pruriens efficiently recovers the spermatogenic loss induced due to EE administration. The recovery is mediated by reduction in ROS level, restoration of MMP, regulation of apoptosis and eventual increase in the number of germ cells and regulation of apoptosis. The present study simplified the complexity of mechanism involved and provided meaningful insights into MP/LD mediated correction of spermatogenic impairment caused by estrogens exposure. This is the first study demonstrating that L-DOPA largely accounts for pro-spermatogenic properties of M. pruriens. The manuscript bears CDRI communication number 8374.
HubMed – drug

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