Polyene Motifs Made Easier by the Dozen
New straightforward synthetic approach can build thousands of polyene motifs from 12 chemical building blocks
A group at the University of Illinois (IL, USA) has designed a technique that is capable of synthesizing thousands of polyene natural product motifs, which exhibit strong potential as drugs, using a simple and economic method that employs only a dozen different building blocks.
The platform is reportedly able to create a wide range of polyene frameworks using the same general retrosynthetic algorithm and reaction conditions, thereby supporting the hypothesis that many small molecules, such as polypeptides, oligonucleotides and oligosaccharides, possess inherent modularity commensurate with systematic building block-based construction. The team succeeded in synthesizing polyene motifs found in >75% of all known polyene natural products and achieved the first total syntheses of polyene natural products asnipyrone B, physarigin A and neurosporaxanthin β-d-glucopyranoside.
“In the same way that plastic building blocks of different sizes and shapes can snap together because they share a simple connector, the chemical building blocks are linked together with one simple reaction,” explained Martin Burke, leader of the research project and a professor at the University of Illinois. “This gives scientists freedom to build molecules that may be difficult or expensive to extract from their natural source or to make in a lab,” he added.
The team envisages that by identifying the required building blocks and making them widely available, current understanding of polyene natural products will be broadened, compounds that were once too expensive or time consuming to make will no longer be left unexplored, and the drug-like potential of polyenes will become fully exploited.
In terms of future work, Burke commented that the team are “Committed to figuring out a global collection of building blocks – how to make them, how to put them together – to create a generalized approach for small-molecule synthesis.”
– Written by Hannah Coaker
Sources: Woerly EM, Roy J, Burke MD. Synthesis of most polyene natural product motifs using just 12 building blocks and one coupling reaction. Nat. Chem. 6(6), 484–491 (2014); Making better medicines with a handful of chemical building blocks:http://news.illinois.edu/news/14/0519polyenes_MartinBurke.html
Scientists Uncover the Potential of Marijuana in Treating Autoimmune Disease
A team, from the University of South Carolina (SC, USA), have reported on a novel pathway through which marijuana’s main active constituent, Δ9-tetrahydrocannabinol (THC), can be used to modulate the body’s immune system.
Marijuana is currently used regularly and successfully in the clinic for a variety of purposes. For example, in order to alleviate side effects of chemotherapy, such as nausea and vomiting, and to combat the wasting syndrome that causes some AIDS patients to lose significant amounts of weight and muscle mass.
In a study led by Mitzi Nagarkatti, a scientist at the University of South Carolina, yet another potential therapeutic application of marijuana was identified, in the suppression of immune response to treat autoimmune diseases.
The team employed ChIP–Seq technology to examine the in vivo effect of THC on global histone methylation in lymph node cells of mice immunized with the superantigen, staphylococcal enterotoxin B. The group then compared genome-wide histone H3K4, H3K27, H3K9, H3K36 trimethylation and H3K9 acetylation patterns after exposure of the cells to THC or vehicle. The results of the study indicated that THC treatment leads to active histone modification signals to Th2 cytokine genes and suppressive modification signals to Th1 cytokine genes, demonstrating that such a mechanism may play a critical role in the THC-mediated switch from Th1 to Th2.
In addition, the group discovered that, at the global level, a significant portion of histone methylation and acetylation regions were altered by THC; however, the overall distribution of these histone methylation signals among the genomic features were not altered significantly by THC. As such, the team concluded that THC activates the expression of one subset of genes while suppressing the expression of another through histone modification. Functional classification of these histone marker-associated genes showed that these differentially associated genes were involved in various cellular functions, from cell cycle regulation to metabolism, suggesting that THC had a pleiotropic effect on gene expression in immune cells.
Ultimately, the study demonstrates, for the first time, that THC may modulate immune response through epigenetic regulation, thereby indicating the potential application of THC in the treatment of autoimmune diseases such as arthritis, lupus, colitis and multiple sclerosis, in which chronic inflammation plays a central role.
– Written by Hannah Coaker
Sources: Yang X, Hegde VL, Rao R et al. Histone modifications are associated with Delta(9)-tetrahydrocannabinol-mediated alterations in antigen-specific T cell responses. J. Biol. Chem. 289(27), 18707–18718 (2014).
‘Nanodaisy’ Delivery of Anticancer Drugs
Researchers at the North Carolina State University and University of North Carolina at Chapel Hill (USA) have formulated a nanoscale structure in the form of a flower, which they use to deliver anticancer drugs to cancer cells.
Polyethylene glycol (PEG) is a hydrophilic polymer with short strands branching off longer strands. The researchers linked camptothecin (CPT) – an anticancer drug – directly to the shorter strands of PEG, and mixed another anticancer drug called doxorubicin (Dox) into the PEG solution. Because CPT and Dox are both hydrophobic, they cluster together with PEG strands on the outside, making daisy-shaped balls of approximately 50 nm in diameter.
The researchers tested this anticancer drug cocktail in various cell lines, as well as in a murine model of lung cancer. “We found that this technique was much better than conventional drug-delivery techniques at inhibiting the growth of lung cancer tumors in mice,” said Zhen Gu, senior author of the paper. “And based on in vitro tests in nine different cell lines, the technique is also promising for use against leukemia, breast, prostate, liver, ovarian and brain cancers.”
PEG is believed to prolong the drugs’ life when the ‘nanodaisies’ are injected into the bloodstream. After reaching the cancer cells, the drugs are released. “Both drugs attack the cell’s nucleus, but via different mechanisms,” said Wanyi Tai, lead author and a former postdoctoral researcher in Gu’s laboratory.
“Combined, the drugs are more effective than either drug is by itself,” said Gu. “We are very optimistic about this technique and are hoping to begin preclinical testing in the near future.”
– Written by Duc Le
Sources: Tai W, Mo R, Lu Y, Jiang T, Gu Z. Folding graft copolymer with pedant drug segment for co-delivery of anticancer drugs. Biomaterials 35(25), 7194–7203 (2014); North Carolina State University (USA) Press Release:http://news.ncsu.edu/releases/gu-nanodaisy-cancer-2014
Nanoviricides Designed Novel Drug Candidates for Middle East Respiratory Syndrome
Middle East respiratory syndrome (MERS) is a new coronavirus similar to the SARS virus. First appearing in the Middle East in 2012, it has caused approximately 400 cases of infection of which a third was fatal, according to the WHO. In May 2014, the New York Times reported the first MERS case in the USA. Although the virus does not spread easily among humans, there are outbreaks in individuals with close contacts, such as in family and hospital settings.
NanoViricides Inc. (CT, USA) has recently reported that it has designed and synthesized novel nanoviricides® drug candidates against MERS virus in sufficient amount ready for animal experiments. Ligands that are similar to DPP-IV – the host cell receptor that binds to the MERS virus’s spike protein – are designed and chemically attached to nanomicelle base polymers to make the nanoviricides drug candidates.“ The rapid development and deployment capability of our platform technology was demonstrated by how quickly we were able to create these drug candidates,” said Eugene Seymour, chief executive officer of NanoViricides. “The design of a set of viable ligands was completed in merely 3 weeks, and the initial syntheses took another 4 weeks.”
Currently there are no available drugs or vaccines for MERS. No animal models for testing MERS drugs/vaccines exists except for a mouse model recently reported in the Proceedings of the National Academy of Sciences of the USA. In that article, Perlman and colleagues delivered an adenovirus carrying the DPP-IV gene into mice in order to induce MERS virus susceptibility in these animals.
“We have a very high expectation that these drug candidates will show significant effectiveness in combatting the MERS virus infection, based on our work against influenza, HIV, HSV, and other diseases where information on the virus-host cell binding was available,” said Anil R Diwan, president and chairman of NanoViricides. “Further, we have already established that the several nanoviricides we currently have in development are very safe in preliminary animal studies.”
NanoViricides currently has several drug candidates in its pipeline based on its nanoviricide platform technology, such as FluCide™, HIVCide™, HerpiCide™ andDengueCide™. An advantage of this nanoviricide platform is that the drug production can be scaled up easily to large quantity for human use if necessary.
– Written by Duc Le
– Sources: Zhao J, Lib K, Wohlford-Lenaneb C et al. Rapid generation of a mouse model for Middle East respiratory syndrome. Proc. Natl Acad. Sci. USA 111(13), 4970–4975 (2014); NanoViricides Inc. (CT, USA) Press Releases:http://www.nanoviricides.com; New York Times, 2 May 2014:http://www.nytimes.com/2014/05/03/health/mers-virus-found-in-united-states-for-first-time.html?_r=0
Scientists Elucidate the Composition of RNA Ligase
A group at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (Vienna, Austria) has identified the final component that converts RNA ligase into a fully viable enzyme in humans, thereby providing perspectives for new treatment strategies for numerous types of breast cancer and leukemia.
RNA ligases have essential roles in many cellular processes in eukaryotes, archaea and bacteria, including in RNA repair and stress-induced splicing of mRNA. “We already know from studies on yeasts that ligases are involved in defending cells from stress factors,” said Javier Martinez, lead author of the study. “These functions are highly probable in mammal cells as well, and could be a new starting point for cancer therapies – especially for the treatment of various types of breast cancer and leukemia.”
In previous studies the team had identified the human tRNA splicing ligase, a multimeric protein complex with RTCB as the essential subunit. In their most recent study, the group describes the discovery of the important protein, archease, which is bonded to the ligase. Archease was found to be vital in ensuring full activity of the human tRNA ligase complex and significant in facilitating the formation of an RTCB-guanylate intermediate central to mammalian RNA ligation.
Johannes Popow, a member of the group who was responsible for this breakthrough, explains, “By understanding the composition of ligase we will now be able to examine the function of this important enzyme more closely, and possibly apply the results for medical science.”
– Written by Hannah Coaker
Sources: Popow J, Jurkin J, Schleiffer A, Martinez J. Analysis of orthologous groups reveals Archease and DDX1 as tRNA splicing factors. Nature 511(7507), 104–107 (2014); New strategy to avoid collateral damage in cancer:www.imba.oeaw.ac.at/news-media/news/news/new-strategy-to-avoid-collateral-damage-in-cancer/?cHash=c900a6c4d2c249e547a2b8d1283b6741