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PostPosted: Sat Aug 06, 2011 11:08 am 
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Scientists have developed a new class of molecules that target our cells' ticketing and entry system to ensure those with evil intentions do not gain access. The molecules, named pitstops, could lead to new therapeutic approaches to prevent the spread of viral and bacterial infections. The study, which is published today in the journal Cell, is the result of collaboration between researchers in Australia and Germany. Senior author Professor Adam McCluskey and his team at The University of Newcastle designed the pitstops, which successfully block a process called clathrin-mediated endocytosis.

Endocytosis is a process that permits signalling molecules, such as neurotransmitters, hormones and nutrients, to pass through the cell membrane and into the cell. However, the same process is hijacked by numerous bacteria and viruses that include HIV, Hepatitis C and Ebola. And, once inside the cell, viruses take control of its machinery so that they can replicate and spread infection.

Entry pass

In clathrin-mediated endocytosis, clathrin proteins collect at the cell's surface and form a cage-like structure around the cargo destined for entry. McCluskey says that his German colleagues screened about 20,000 commercially available compounds in an attempt to find molecules that block clathrin. "They came up with a couple of hits, but they had poor activity. I got to see the chemical structures, they were hideously complicated."

McCluskey's job was to take the complicated molecules and make them simple. Their starting point was the 3D arrangement of the atoms. "What you are really looking for is the key interaction of the molecules with the [clathrin] protein." "We tried to pull away from what I typically describe as the shrubbery that's on the trees - all those extra leaves that aren't necessary."

Access denied

They found there were three parts to the structure that were important in blocking clathrin and designed and generated a library of compounds for biological evaluation. "These molecules have to get in and out of cells," says McCluskey. "They have to be active and, from my point of view, easy to make." Two molecules came up with the goods: pitstop 1 and pitstop 2. "The idea that blocking clathrin might be a broad-spectrum antiviral treatment excites me," McCluskey says. "We can already see multiple possibilities." Large amounts of clathrin are also found in the brain where they play a vital role in nerve cell signalling.

Pitstop 1 and pitstop 2 were also tested for their ability to block nerve cell signalling in a whole animal model: the Lamprey eel. They were found to be effective.

Dr Brett Collins, a protein chemist, at the Institute for Molecular Bioscience in Queensland describes this paper as a "major breakthrough". "Previously, genetic approaches would have been used to look at these [clathrin-mediated] processes," he says. "But the problem is these approaches take time and it can be days before you have an effect. With these small molecules you can get results instantly and attribute these functional impacts directly to the clathrin molecules."

Collins expects that the pitstop molecules will now be used by researchers worldwide in experiments designed to better understand clathrin-mediated endocytosis. "It's an area of major interest: not just which proteins bind to which, but the timing and the dynamics of the process." He says the pitstop molecules have potential for treating certain neurological disorders, such as epilepsy, where there is an overstimulation of nerve cells. But Collins notes that the pitstop molecules described in the paper will need further modifications before they are 'drug quality.'

In true research style, Adams says they have already produced the next generation of pitstops that will hopefully be more potent. "We are at a hugely exciting stage ....already our colleagues at the Children's Medical Research Institute [in Sydney] have some interesting data for novel modes of action for an anticancer effect."

Source: ABC Health - ... te=science

I'm really excited by this research. If they can prevent viral replication this could mean that one day soon they will be able to stop cancer in it's tracks.
YouTube has a few good videos if you're interested in watching this effect in action...

The virus entry system ... re=related


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