Medical experts launch crowd funding project to investigate effect of malaria drug on colorectal cancer

In continuation of my update on Artesunate

Medical experts investigating whether a common malaria drug could have a significant impact on colorectal cancer have launched a crowd funding project to fund their work.

Scientists at St George's, University of London, and St George's Hospital, are in the second phase of research into whether the malaria drug artesunate, can have a positive effect on colorectal cancer patients by reducing the multiplication of tumour cells and decreasing the risk of cancer spreading or recurring after surgery. If it does the drug could be used to provide a cheap adjunct to current expensive chemotherapy.

Artesunate is derived from the plant Artemisia Annua also known as Sweet Wormwood. The Chinese scientist Tu Youyou whose research in the 1960s led to the development of artesunate from a plant used in Chinese traditional medicine, was recently awarded the Nobel Prize 2015.

Over one million patients are diagnosed with colorectal cancer globally each year. Colorectal cancer is the third most common cancer in men and the second most common cancer in women and is a leading cause of mortality. In the UK,110 new cases are diagnosed daily, with older patients particularly at risk of death (Ferlay et al 2014). Current treatments involve complex combinations of surgery, chemotherapy and radiotherapy.

Unfortunately all these measures have not increased overall survival rates beyond 60% at the 5 year stage after patients receive a diagnosis. New treatments are urgently needed to improve survival rates. Developing new, effective drugs however can take many years and sometimes even decades. Repurposing safe and established existing drugs for cancer treatment is therefore gaining interest amongst the scientific community.

Medical experts launch crowd funding project to investigate effect of malaria drug on colorectal cancer

New class of highly potent antimalarial compounds discovered

In a recent work published online today in the journal PNAS, researchers at the Instituto de Medicina Molecular (IMM), in Lisbon, Portugal, have discovered a new class of highly potent antimalarial compounds. These compounds, referred to as Torins, were originally developed by researchers in the Boston, MA to inhibit a key human protein involved in cell growth, mTOR, and have been shown to be effective anticancer agents in rodent models. In research perdormed by Dr. Kirsten Hanson in the laboratory of Dr. Maria Mota, the IMM team and their collaborators have discovered that Torins are extremely effective multistage antimalarials; Torins appear to have a novel activity against the Plasmodium parasites themselves, distinct from both currently used malaria therapeutics and from their ability to target human mTOR.

Torins are capable of killing the cultured blood stages of the human parasite, Plasmodium falciparum, the species which causes most malaria deaths and severe disease, and are equally potent against the liver stages of a model rodent parasite. A single dose of the compound Torin2 delivered at the beginning of the P. berghei liver stage is sufficient to eliminate infection in mice before any Plasmodium parasites reach the blood. "Given the alarming trend of resistance to our current antimalarial therapies, this is really an exciting finding," says Dr. Mota, the senior author of the study, "and we are already working to develop Torin molecules suitable for clinical trials of antimalarial activity in humans."

 Ref : http://www.pnas.org/content/early/2013/07/03/1306097110.full.pdf+html

New class of highly potent antimalarial compounds discovered

Research aims for insecticide that targets malaria mosquitoes

Acetylcholinesterase helps regulate nervous system activity by stopping electrical signaling in nerve cells. If the enzyme can't do its job, the mosquito begins convulsing and dies. The research team's goal is to develop compounds perfectly matched to the acetylcholinesterase molecules in malaria-transmitting mosquitoes, he said.

"A simple analogy would be that we're trying to make a key that fits perfectly into a lock," Bloomquist said. "We want to shut down the enzyme, but only in target species."

Bloomquist and colleagues at Virginia Tech, where the project is based, are trying to perfect mosquito-specific compounds that can be manufactured on a large scale and applied to mosquito netting and surfaces where the pests might land.

It will take at least four to five years before the team has developed and tested a compound enough that it's ready to be submitted for federal approval, Bloomquist said.

As per the claims by the researchers, conventional insecticides targeting acetylcholinesterase (AChE) typically show high mammalian toxicities and because there is resistance to these compounds in many insect species, alternatives to established AChE inhibitors used for pest control are needed. Here researchers  used a fluorescence method to monitor interactions between various AChE inhibitors and the AChE peripheral anionic site, which is a novel target for new insecticides acting on this enzyme. The assay uses thioflavin-T as a probe, which binds to the peripheral anionic site of AChE and yields an increase in fluorescent signal. Three types of AChE inhibitors were studied: catalytic site inhibitors (carbamate insecticides, edrophonium, and benzylpiperidine), peripheral site inhibitors (tubocurarine, ethidium bromide, and propidium iodide), and bivalent inhibitors (donepezil, BW284C51, and a series of bis(n)-tacrines). All were screened on murine AChE to compare and contrast changes of peripheral site conformation in the TFT assay with catalytic inhibition. All the inhibitors reduced thioflavin-T fluorescence in a concentration-dependent manner with potencies (IC₅₀) ranging from 8 nM for bis(6)-tacrine to 159 μM for benzylpiperidine. Potencies in the fluorescence assay were correlated well with their potencies for enzyme inhibition (R² = 0.884). Efficacies for reducing thioflavin-T fluorescence ranged from 23–36% for catalytic site inhibitors and tubocurarine to near 100% for ethidium bromide and propidium iodide. Maximal efficacies could be reconciled with known mechanisms of interaction of the inhibitors with AChE. When extended to pest species, we anticipate these findings will assist in the discovery and development of novel, selective bivalent insecticides acting on AChE....

 Ref : http://www.sciencedirect.com/science/article/pii/S0048357513000655#f0025

Research aims for insecticide that targets malaria mosquitoes

New low-cost combined therapy shows promise against malaria

Molecular parasitologist Stephen Rich at the University of Massachusetts Amherst has led a research team who report a promising new low-cost combined therapy with a much higher chance of outwitting P. falciparum than current modes. He and plant biochemist Pamela Weathers at the Worcester Polytechnic Institute (WPI), with research physician Doug Golenbock at the UMass Medical School, also in Worcester, have designed an approach for treating malaria based on a new use of Artemisia annua, a plant employed for thousands of years in Asia to treat fever.

"The emergence of resistant parasites has repeatedly curtailed the lifespan of each drug that is developed and deployed," says UMass Amherst graduate student and lead author Mostafa Elfawal. Rich, an expert in the malaria parasite and how it evolves, adds, "We no sooner get the upper hand than the parasite mutates to become drug resistant again. This cycle of resistance to anti-malarial drugs is one of the great health problems facing the world today. We're hoping that our approach may provide an inexpensive, locally grown and processed option for fighting malaria in the developing world."

Currently the most effective malaria treatment uses purified extracts from the Artemisia plant as part of an Artemisinin Combined Therapy (ACT) regime with other drugs such as doxycycline and/or chloroquine, a prescription far too costly for wide use in the developing world. Also, because Artemisia yields low levels of pure artemisinin, there is a persistent worldwide shortage, they add.

The teams's thesis, first proposed by Weathers of WPI, is that locally grown and dried leaves of the whole plant, rich in hundreds of phytochemicals not contained in the purified drug, might be effective against disease at the same time limiting post-production steps, perhaps substantially reducing treatment cost. She says, "Whole-plant Artemisia has hundreds of compounds, some of them not even known yet. These may outsmart the parasites by delivering a more complex drug than the purified form."

Rich adds, "The plant may be its own complex combination therapy. Because of the combination of parasite-killing substances normally present in the plant (artemisinin and flavonoids), a synergism among these constituent compounds might render whole plant consumption as a form of artemisinin-based combination therapy, or what we're calling a 'pACT,' for plant Artemisinin Combination Therapy."

Ref : http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0052746

New low-cost combined therapy shows promise against malaria

Anti-malaria drug synthesised with the help of oxygen and light

In continuation of my update, artemisinin... The most effective anti-malaria drug can now be produced inexpensively and in large quantities. This means that it will be possible to provide medication for the 225 million malaria patients in developing countries at an affordable price. Researchers at the Max Planck Institute of Colloids and Interfaces in Potsdam and the Freie Universität Berlin have developed a very simple process for the synthesis of artemisinin, the active ingredient that pharmaceutical companies could only obtain from plants up to now. The chemists use a waste product from current artemisinin production as their starting substance. This substance can also be produced biotechnologically in yeast, which the scientists convert into the active ingredient using a simple yet very ingenious method..... Look at http://www.mpg.de/4984709/artemisinin_malaria

Researchers discover new class of antimalarial compounds...

Researchers have discovered a group of chemical compounds that might one day be developed into drugs that can treat malaria infection in both the liver and the bloodstream. The study, which appears in the Nov. 18 issue of Science, was led by Elizabeth A. Winzeler, Ph.D., of the Scripps Research Institute in La Jolla, Calif., and was partially funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

By screening more than 4,000 chemical compounds that had previously shown activity against blood-stage Plasmodium, the investigators searched for a compound that would also inhibit liver-stage parasites and whose protein structure would allow the modification necessary for future drug development. They found that a group of three related compounds, known collectively as the imidazolopiperazine (IP) cluster, fit these criteria. In addition, strains of Plasmodium that had acquired resistance to other malaria drugs were susceptible to the IP cluster.

Using the IP cluster as a foundation, the researchers designed a drug candidate, GNF179, that reduced levels of one Plasmodium species by 99.7 percent and extended survival by an average of 19 days when tested in malaria-infected mice. By examining infected cells, the researchers confirmed that GNF179 (see the structure) was active in the liver stage of infection. Rresearchers note that while additional studies will be needed to fully understand the drug's mechanism of action and its specific targets within the liver, this study provides a potential starting point for developing new dual-stage antimalarial drugs.....

More : http://www.sciencemag.org/content/early/2011/11/16/science.1211936.abstract