Featured Research

from universities, journals, and other organizations

Compound stymies polyomaviruses in lab tests

Date:
November 13, 2013
Source:
Brown University
Summary:
There is no approved medicine to treat polyomaviruses, which afflict those with weakened immune systems, but scientists have found that a chemical compound called Retro-2 is able to significantly reduce the infectivity and spread of the viruses in lab cell cultures. Now they are working to improve it further.

Other substances can control the polyoma virus only if they were administered prior to infection. In cell culture studies, Retro-2 appears to control the infectivity and spread of polyomavirus even when the virus is already established.
Credit: Atwood lab/Brown University

A team of scientists reports that a small-molecule compound showed significant success in controlling the infectivity and spread of three polyomaviruses in human cell cultures. To date there has been no medicine approved to treat such viruses, which prey on transplant recipients, people with HIV, and others whose immune systems have been weakened.

The compound, known by the abbreviated name "Retro-2," was able to protect the vast majority of cells in cultures when it was administered even after infection began. According to results published in the journal mBio, 12 days of treatment with Retro-2 kept 90.5 percent of cells free from JC polyomavirus, 89 percent of cells clear of the BK polyomavirus, and 84 percent of cells protected from the SV40 polyomavirus. Infection rates and virus production were much higher among cells in cultures that were similarly infected but left untreated as controls.

That the compound gained the upper hand on viruses that had a head start is a key advance, said Brown University biologist Walter Atwood, corresponding author of the paper. Other substances have defeated the viruses only if they were used to pre-treat cells before any infection.

"But that's not reality," Atwood said. "The reality is that someone is already infected with the virus. Whenever in the past we first infected the cells with the virus and then came in with the drug, we've never been successful in being able to stop the spread of the virus. This drug is successful at that."

Brown University has a patent filed on the use of the compound against pathogen infections. The research also involved a team of scientists at Yale University led by Daniel DiMaio.

An 'ER' medicine

Retro-2 appears to work by blocking the ability of polyomaviruses to sneak around host cells by hijacking the intracellular protein transportation hub: the endoplasmic reticulum (ER).

Christian Nelson, a Brown postdoctoral researcher currently visiting at Yale, first thought to study Retro-2 after reading a 2010 paper in Cell showing that it blocks certain toxins, including ricin, from working through the ER. Ricin and polyomaviruses have been thought to operate similarly. The compound also did not appear to be toxic to the mice in that study.

"There are a lot of viruses that use these trafficking mechanisms," Atwood said.

So the team bought some Retro-2 from Chembridge, a company that makes vast libraries of small-molecule compounds for scientists to study, and pitted it against the polyomaviruses.

The researchers tested it in several ways, including with both kidney cells and brain cells because those are the tissues in the body where they can cause disease. Retro-2 appeared effective in protecting the various cells, as long as it was present within several hours of infection.

"When this causes disease in people, there's progressively more and more cells infected," Nelson said. "If we can identify infection early, a treatment could help to stop that progression."

Improving the chemistry

Atwood and Nelson acknowledge that they aren't yet sure exactly how Retro-2 blocks the viruses in the ER, but thanks to a team of collaborating chemists, they do know what chemical structure makes the drug effective.

Brown chemistry professors Jason Sello and Paul Williard and graduate student Daniel Carney studied the compound's chemical structure. In efforts to prepare Retro-2, Sello and Carney found that the last step in the synthesis yielded not only the reported structure but also a form called a dihydroquinazolinone (DHQ). The DHQ was the apparent result of a "cyclizing" reaction of Retro-2 that gives it a different chemical structure.

Further experiments identified the exact structure of the DHQ form and showed that it was the form that matched what Atwood and Nelson had found to be effective in the lab.

This detailed understanding of the compound is helping Sello and his team improve the drug further.

"A critical part of any drug development program is the unambiguous assignment of the structure of the lead compound," Sello said. "With knowledge of the Retro-2 structure, we have been rationally preparing analogs that have improved pharmacological properties."


Story Source:

The above story is based on materials provided by Brown University. Note: Materials may be edited for content and length.


Journal Reference:

  1. C. D. S. Nelson, D. W. Carney, A. Derdowski, A. Lipovsky, G. V. Gee, B. O'Hara, P. Williard, D. DiMaio, J. K. Sello, W. J. Atwood. A Retrograde Trafficking Inhibitor of Ricin and Shiga-Like Toxins Inhibits Infection of Cells by Human and Monkey Polyomaviruses. mBio, 2013; 4 (6): e00729-13 DOI: 10.1128/mBio.00729-13

Cite This Page:

Brown University. "Compound stymies polyomaviruses in lab tests." ScienceDaily. ScienceDaily, 13 November 2013. <www.sciencedaily.com/releases/2013/11/131113130031.htm>.
Brown University. (2013, November 13). Compound stymies polyomaviruses in lab tests. ScienceDaily. Retrieved July 23, 2014 from www.sciencedaily.com/releases/2013/11/131113130031.htm
Brown University. "Compound stymies polyomaviruses in lab tests." ScienceDaily. www.sciencedaily.com/releases/2013/11/131113130031.htm (accessed July 23, 2014).

Share This




More Plants & Animals News

Wednesday, July 23, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Michigan Plant's Goal: Flower and Die

Michigan Plant's Goal: Flower and Die

AP (July 22, 2014) An 80-year-old agave plant, which is blooming for the first and only time at a University of Michigan conservatory, will die when it's done (July 22) Video provided by AP
Powered by NewsLook.com
San Diego Zoo Welcomes New, Rare Rhino Calf

San Diego Zoo Welcomes New, Rare Rhino Calf

Reuters - US Online Video (July 21, 2014) An endangered black rhino baby is the newest resident at the San Diego Zoo. Sasha Salama reports. Video provided by Reuters
Powered by NewsLook.com
Shark Sightings a Big Catch for Cape Tourism

Shark Sightings a Big Catch for Cape Tourism

AP (July 21, 2014) A rise in shark sightings along the shores of Chatham, Massachusetts is driving a surge of eager vacationers to the beach town looking to catch a glimpse of a great white. (July 21) Video provided by AP
Powered by NewsLook.com
$23.6 Billion Awarded To Widow In Smoking Lawsuit

$23.6 Billion Awarded To Widow In Smoking Lawsuit

Newsy (July 20, 2014) Cynthia Robinson claims R.J. Reynolds Tobacco Company hid the health and addiction risks of its products, leading to the death of her husband in 1996. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins