Local researcher stumbles upon a possible Ebola treatment

Howard University Professor Sergei Nekhai says that while the Ebola & HIV viruses are not the same, the way they reproduce in the cells are.

http://m.wusa9.com/health/article?a=15449653&f=234

http://pipeline.corante.com/archives/2014/09/26/pains_go_mainstream.php

...Academic researchers, drawn into drug discovery without appropriate guidance, are doing muddled science. When biologists identify a protein that contributes to disease, they hunt for chemical compounds that bind to the protein and affect its activity. A typical assay screens many thousands of chemicals. ‘Hits’ become tools for studying the disease, as well as starting points in the hunt for treatments. But many hits are artefacts — their activity does not depend on a specific, drug-like interaction between molecule and protein. A true drug inhibits or activates a protein by fitting into a binding site on the protein. Artefacts have subversive reactivity that masquerades as drug-like binding and yields false signals across a variety of assays....

... A literature search reveals 2,132 rhodanines reported as having biological activity in 410 papers, from some 290 organizations of which only 24 are commercial companies. The academic publications generally paint rhodanines as promising for therapeutic development. In a rare example of good practice, one of these publications (by the drug company Bristol-Myers Squibb) warns researchers that these types of compound undergo light-induced reactions that irreversibly modify proteins. It is hard to imagine how such a mechanism could be optimized to produce a drug or tool. Yet this paper is almost never cited by publications that assume that rhodanines are behaving in a drug-like manner.

Very occasionally, a PAINS compound does interact with a protein in a specific drug-like way. If it does, its structure could be optimized through medicinal chemistry. However, this path is fraught — it can be difficult to distinguish when activity is caused by a drug-like mechanism or something more insidious. Rhodanines also occur in some 280 patents, a sign that they have been selected for further drug development. However, to our knowledge, no rhodanine plucked out of a screening campaign is in the clinic or even moving towards clinical development. We regard the effort to obtain and protect these patents (not to mention the work behind them) as a waste of money. ...

Researchers Pinpoint Origin of HIV Pandemic

A group of researchers from Oxford University and the University of Leuven say they have pinpointed the place where HIV was first transmitted between humans, sparking a pandemic that would go on to touch some 75 million people in every corner of the globe.

Through statistical analysis, the group determined that HIV is "almost certain" to have begun its spread from Kinshasa, now the capital city of the Democratic Republic of Congo, sometime around 1920.

http://www.msn.com/en-us/news/world/researche...f-hiv-pandemic/ar-BB740Xi

http://www.medicalnewstoday.com/releases/283601.php

9 October 2014

"Computers are powerful allies in the fight against AIDS

The battle against AIDS cannot be won in the laboratory alone. To fight the potentially deadly virus that 34 million people are suffering from we need help from computers. Now research from University of Southern Denmark turns computers into powerful allies in the battle.

Effective treatment of HIV-virus is a race against time: Many of the drugs that have been potent killers of HIV-virus, have today lost their power, because the virus has become resistant to them. As a result science must constantly develop new drugs that can attack the virus in new ways.

Now researchers from the University of Southern Denmark present a method to speed up the important development work up with an order of several hundred percent.

It now takes not years, but months or even only weeks to find new compounds that have the potential to become a new HIV drug. Finding suitable compounds that can specifically inhibit the HIV virus, is crucial in AIDS research, explains postdoc Vasantanathan Poongavanam from Department of Physics, Chemistry and Pharmacy, University of Southern Denmark:

"HIV is a retrovirus that contains enzymes which make it able to copy itself with the help of host genetic material and thus reproduce. If you can block these enzymes' ability to replicate itself, the virus cannot reproduce."

The needle in the haystack

An almost infinite number of different substances can be synthetized in a laboratory. Some of them may prove to inhibit HIV-virus's reproduction, but finding them is like finding a needle in a haystack.

"It takes enormous amounts of time and resources, to go through millions and millions of compounds. With the techniques used today, it may take years to carry out a screening of possible compounds".

In addition, it takes time to turn an effective compound into a safe pharmaceutical agent that can get on the market.

"Today, it generally takes nearly 14 years from the time you find a drug candidate to get it on the market. Anything that can shorten that time is an important improvement", says Vasanthanathan Poongavanam.

Until now, researchers have been hampered by slow computers and inaccurate prediction models when they ask computers to identify compounds that may be effective against HIV. Now the SDU researchers have managed to develop an effective model at a time when significantly more powerful computers have become available.

"Our work shows that computer based predictions are a extremely fast, accurate and promising methodology in the drug discovery projects", says Vasanthanathan Poongavanam.

14 new compounds found

With the new methods based on quantum mechanics and molecular mechanics, Vasanthanathan Poongavanam and his colleague, Jacob Kongsted, screened half a million compounds and found 25 that were interesting to investigate further. These 25 were tested in a conventional laboratory experiment, and 14 of them were found to inhibit HIV virus's ability to reproduce.

"It took us only a few weeks to find these 14 very interesting compounds, whereas before it would have taken years", explains Vasanthanathan Poongavanam.

The 14 compounds have now been taken over by Italian researchers who continue working with them at the University of Cagliari. The next step is to carry out advanced experiments on these compounds. If they are positive, the compounds may go on the market as a drug against HIV.

The description of the new method are published in the journals Integrative Biology and Plos One."

http://www.medicalnewstoday.com/releases/281801.php

3 September 2014

"Inflammatory response in early HIV breaks down intestinal lining, but help may come from friendly bacteria

Researchers at UC Davis have made some surprising discoveries about the body's initial responses to HIV infection. Studying simian immunodeficiency virus (SIV), the team found that specialized cells in the intestine called Paneth cells are early responders to viral invasion and are the source of gut inflammation by producing a cytokine called interleukin-1 beta (IL-1β).

Though aimed at the presence of virus, IL-1β causes breakdown of the gut epithelium that provides a barrier to protect the body against pathogens. Importantly, this occurs prior to the wide spread viral infection and immune cell killing. But in an interesting twist, a beneficial bacterium, Lactobacillus plantarum, helps mitigate the virus-induced inflammatory response and protects gut epithelial barrier. The study was published in the journal PLoS Pathogens.

One of the biggest obstacles to complete viral eradication and immune recovery is the stable HIV reservoir in the gut. There is very little information about the early viral invasion and the establishment of the gut reservoir.

"We want to understand what enables the virus to invade the gut, cause inflammation and kill the immune cells," said Satya Dandekar, lead author of the study and chair of the Department of Medical Microbiology and Immunology at UC Davis.

"Our study has identified Paneth cells as initial virus sensors in the gut that may induce early gut inflammation, cause tissue damage and help spread the viral infection. Our findings provide potential targets and new biomarkers for intervening or blocking early spread of viral infection," she said.

In the study, the researchers detected a very small number of SIV infected cells in the gut within initial 2.5 days of viral infection; however, the inflammatory response to the virus was playing havoc with the gut lining. IL-1β was reducing the production of tight-junction proteins, which are crucial to making the intestinal barrier impermeable to pathogens. As a result, the normally cohesive barrier was breaking down.

Digging deeper, the researchers found the inflammatory response through IL-1β production was initiated in Paneth cells, which are known to protect the intestinal stem cells to replenish the epithelial lining. This is the first report of Paneth cell sensing of SIV infection and IL-1β production that links to gut epithelial damage during early viral invasion. In turn, the epithelial breakdown underscores that there's more to the immune response than immune cells.

"The epithelium is more than a physical barrier," said first author Lauren Hirao. "It's providing support to immune cells in their defense against viruses and bacteria."

The researchers found that addition of a specific probiotic strain, Lactobacillus plantarum, to the gut reversed the damage by rapidly reducing IL-1β, resolving inflammation, and accelerating repair within hours. The study points to interesting possibilities of harnessing synergistic host-microbe interactions to intervene early viral spread and gut inflammation and to mitigate intestinal complications associated with HIV infection.

"Understanding the players in the immune response will be important to develop new therapies," said Hirao. "Seeing how these events play out can help us find the most opportune moments to intervene."