Die behandeling van VIGS - Geneesmiddels en vaksiene - Wat hou die toekoms in?

The developing epidemic of acquired immunodeficiency syndrome (AIDS) has prompted a broadly based research effort to find drugs and vaccines for preventing and treating this disease. Compounds such as zidovudine (AZT), ampligen and the broad spectrum of pyrimidine dideaxynucleosides have yielded some promise for the treatment of AIDS in terms of better quality of life for sufferers, but no cure is in sight yet. Also the quest for therapeutic and preventative vaccines has also been ongoing for several years. The latest development of the Salk vaccine has led to wild speculation in the lay press of a cure for AIDS. However, some seemingly insurmountable practical and moral-ethical problems beset both the development of AIDS chemotherapy and an AIDS vaccine. The most vexing of these problems is the lack of a suitable animal model for testing and the consequent questions of whether uninfected or HIV-infected but symptom-free volunteers can or should be used in testing potentially lethal compounds or vaccines

Microwave-assisted methods for the synthesis of pentacyclo[5.4.0.02,6.03,10.05,9]undecylamines

Efficient methodologies for the preparation of pentacyclo[5..4.0.02,6.03,10.05,9]undecane (PCU) amine derivatives are described via microwave-assisted synthesis. The obtained results revealed that microwave-assisted synthetic procedures under controlled conditions (power, temperature and time) are very convenient, high yielding, efficient and low-cost methods for the preparation of PCU amine derivatives. The new methods show several advantages including operational simplicity, good performance, significant reduction in reaction time, less by-product formation and easier purification.Web of Scienc

The conformation of (-)-8α- and (-)-8α-hydroxy-Δ9-tetrahydrocannabinols and their interactions with model membranes.

8α- and 8β-Hydroxy-δ9-tetrahydrocannabinols (THC's), two metabolites of the naturally occurring δ9-THC have been shown to possess differences in pharmacological activity. We have studied the conformations of these two compounds, as well as their interactions with model membrane systems and compared them with δ9-THC. The conformational study, carried out in solution and using high resolution NMR indicated that differences in the ring conformations of these two compounds were negligible butthat the 8-hydroxy group of the 8β-OH compound extended approximately 1.4Å higher above the plane of the aromatic ring than in the 8α-OH isomer. This difference could prove significant in the interaction of these molecules with lipid bilayers. We found that both 8α- and 8β-OH analogs affected the melting behavior of hydrated DPPC bilayers including a lowering of the main transition temperature (Tc), a broadening of that transition and the abolishment of the pretransition of DPPC. The effects of the more active compound, 8β-OH-δ9-THC on the model membrane approximated closely those of δ9-THC, while the less active 8α-OH epimer produced different thermotropic changes

Synthesis and biological evaluations of NO-donating oxa- and aza-pentacycloundecane derivatives as potential neuroprotective candidates

In order to utilize the neuroprotective properties of polycyclic cage compounds, and explore the NO-donating ability of nitrophenyl groups, an array of compounds was synthesized where the different nitrophenyl groups were appended on oxa and aza-bridged cage derivatives. Biological evaluations of the compounds were done for cytotoxicity, neuroprotective abilities, the inhibition of N-methyl-D-aspartate (NMDA)-mediated Ca2+ influx, the inhibition of voltage-mediated Ca2+ influx, and S-nitrosylation abilities. All of the compounds showed low toxicity. With a few exceptions, most of the compounds displayed good neuroprotection and showed inhibitory activity for NMDA-mediated and voltage-gated calcium influx, ranging from high (>70%) to low (20–39%) inhibition. In the S-nitrosylation assay, the compounds with the nitro moiety as the NO-donating group exhibited low to good nitrosylation potency compared to the positive controls. From the biological evaluation of the tested compounds, it was not possible to obtain a simple correlation that could explain the results across all of the biological study domains. This can be ascribed to the independent processes evaluated in the different assays, which reiterate that neuroprotection is a result of multifactorial biochemical mechanisms and interactions. However, these results signify the important aspects of the pentacylcoundecylamine neuroprotectants across different biological study realms.IS

Why Do We Need Multifunctional Neuroprotective and Neurorestorative Drugs for Parkinson's and Alzheimer's Diseases as Disease Modifying Agents

Parkinson's disease (PD) and Alzheimer's Disease (AD) are severe neurodegenerative disorders, with no drugs that are currently approved to prevent the neuronal cell loss characteristic in brains of patients suffering from PD and AD and all drug treatment are synptomactic. Due to the complex pathophysiology, including a cascade of neurotoxic molecular events that results in neuronal death and predisposition to depression and eventual dementia and etiology of these disorders, an innovative approach towards neuroprotection or neurorestoration (neurorescue) may be the development and use of multifunctional pharmaceuticals. Such drugs target an array of pathological pathways, each of which is believed to contribute to the cascades that ultimately lead to neuronal cell death. In this short review, we discuss examples of novel multifunctional ligands that may have potential as neuroprotective-neurorestorative therapeutics in PD and AD. The compounds discussed originate from synthetic chemistry as well as from natural sources

3D-QSAR and docking studies of pentacycloundecylamines at the sigma-1 (σ1) receptor

Pentacycloundecylamine (PCU) derived compounds have been shown to be promising lead structures for the development of novel drug candidates aimed at a variety of neurodegenerative and psychiatric diseases. Here we show for the first time a 3D quantitative structure–activity relationship (3D-QSAR) for a series of aza-PCU-derived compounds with activity at the sigma-1 (r1) receptor. A comparative molecular field analysis (CoMFA) model was developed with a partial least squares cross validated (q2) regression value of 0.6, and a non-cross validatedr2 of 0.9. The CoMFA model was effective at predicting the sigma-1 activities of atest set with an r2 >0.7. We also describe here the docking of the PCU-derivedcompounds into a homology model of the sigma-1 (r1) receptor, which was developed to gain insight into binding of these cage compounds to the receptor. Based on docking studies we evaluated in a [3H]pentazocine binding assay anoxa-PCU, NGP1-01 (IC50 = 1.78 lM) and its phenethyl derivative (IC50 = 1.54 lM). Results from these studies can be used to develop new compounds with specific affinity for the sigma-1(r1)Web of Scienc

Multifunctional Compounds for Activation of the p53‐Y220C Mutant in Cancer

The p53 protein plays a major role in cancer prevention, and over 50 % of cancer diagnoses can be attributed to p53 malfunction. The common p53 mutation Y220C causes local protein unfolding, aggregation, and can result in a loss of Zn in the DNA‐binding domain. Structural analysis has shown that this mutant creates a surface site that can be stabilized using small molecules, and herein a multifunctional approach to restore function to p53‐Y220C is reported. A series of compounds has been designed that contain iodinated phenols aimed for interaction and stabilization of the p53‐Y220C surface cavity, and Zn‐binding fragments for metallochaperone activity. Their Zn‐binding affinity was characterized using spectroscopic methods and demonstrate the ability of compounds L4 and L5 to increase intracellular levels of Zn2+ in a p53‐Y220C‐mutant cell line. The in vitro cytotoxicity of our compounds was initially screened by the National Cancer Institute (NCI‐60), followed by testing in three stomach cancer cell lines with varying p53 status’, including AGS (WTp53), MKN1 (V143A), and NUGC3 (Y220C). Our most promising ligand, L5, is nearly 3‐fold more cytotoxic than cisplatin in a large number of cell lines. The impressive cytotoxicity of L5 is further maintained in a NUGC3 3D spheroid model. L5 also induces Y220C‐specific apoptosis in a cleaved caspase‐3 assay, reduces levels of unfolded mutant p53, and recovers p53 transcriptional function in the NUGC3 cell line. These results show that these multifunctional scaffolds have the potential to restore wild‐type function in mutant p53‐Y220C

Modularity in Protein Complex and Drug Interactions Reveals New Polypharmacological Properties

Recent studies have highlighted the importance of interconnectivity in a large range of molecular and human disease-related systems. Network medicine has emerged as a new paradigm to deal with complex diseases. Connections between protein complexes and key diseases have been suggested for decades. However, it was not until recently that protein complexes were identified and classified in sufficient amounts to carry out a large-scale analysis of the human protein complex system. We here present the first systematic and comprehensive set of relationships between protein complexes and associated drugs and analyzed their topological features. The network structure is characterized by a high modularity, both in the bipartite graph and in its projections, indicating that its topology is highly distinct from a random network and that it contains a rich and heterogeneous internal modular structure. To unravel the relationships between modules of protein complexes, drugs and diseases, we investigated in depth the origins of this modular structure in examples of particular diseases. This analysis unveils new associations between diseases and protein complexes and highlights the potential role of polypharmacological drugs, which target multiple cellular functions to combat complex diseases driven by gain-of-function mutations