Featured Research

from universities, journals, and other organizations

New mechanism of blocking HIV-1 from entering cells identified

Date:
December 1, 2009
Source:
Thomas Jefferson University
Summary:
Researchers have found a novel mechanism by which drugs block HIV-1 from entering host cells.

Publishing in PLoS Pathogens, researchers at from the Kimmel Cancer Center at Jefferson have found a novel mechanism by which drugs block HIV-1 from entering host cells.

Cellular invasion by HIV-1 requires the concerted action of two proteins on the viral surface: gp120 and gp41. The function of gp41 is to get the viral contents into the interior of the host cells. This requires the association of two distinct regions of gp41 called N-HR and C-HR. Anti-HIV-1 agents known as fusion inhibitors target the N-HR or C-HR and disrupt their association, which prevents the virus from entering into the host cell. One drug that works like this is Fuzeon (Roche), and there are other agents in the pipeline.

But blocking the N-HR/C-HR association is not only mechanism by which fusion inhibitors prevent HIV-1 entry, according to Michael Root, M.D., Ph.D., assistant professor of Biochemistry and Molecular Biology at Jefferson Medical College of Thomas Jefferson University. The inhibitors also induce irreversible deactivation of gp41.

"After these drugs bind, they seem to shuttle gp41 into a dead conformation from which the protein cannot recover," Dr. Root said. "Importantly, the speed of this drug-induced deactivation greatly influences how potent a drug is at preventing HIV-1 infection."

When the inhibitors bind to the gp41 C-HR, the protein rapidly deactivates before inhibitors have time to dissociate. But when the inhibitors bind to the gp41 N-HR, deactivation takes a very long time, and many inhibitors can readily unbind. To potently inhibit HIV-1 entry, a C-HR targeting fusion inhibitor can have a relatively low affinity, but an N-HR targeting fusion inhibitor must bind extremely tightly.

A major drawback to using Fuzeon and related drugs that target N-HR is the rapid emergence of HIV-1 strains resistant to the drugs. Dr. Root's study suggests that the resistance phenomenon is related to the slow speed of gp41 deactivation induced by these fusion inhibitors. HIV-1 appears to have more difficulty developing resistance to drugs that can remain bound to gp41 for much longer than gp41 takes to deactivate, even if the drugs are no more potent than Fuzeon against the original HIV-1 strain. Armed with this knowledge, Dr. Root and his team have developed a new strategy to improve the antiviral activities of N-HR-targeting fusion inhibitors.

These unexpected properties of HIV-1 fusion inhibitors are a consequence of the short time interval these drugs have to work. The N-HR and C-HR are only accessible to drug binding in a short-lived "intermediate state" that occurs right before N-HR/C-HR association. Most pharmaceutical agents bind targets that exist for long times, but a growing class of drugs target similar, short-lived intermediate states. These drugs include local anesthetics, antibiotics and immunosuppressive agents used in clinical practice. The results of this study might also be extended to understand the activities and limitations of these drugs.


Story Source:

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


Cite This Page:

Thomas Jefferson University. "New mechanism of blocking HIV-1 from entering cells identified." ScienceDaily. ScienceDaily, 1 December 2009. <www.sciencedaily.com/releases/2009/11/091130121445.htm>.
Thomas Jefferson University. (2009, December 1). New mechanism of blocking HIV-1 from entering cells identified. ScienceDaily. Retrieved October 20, 2014 from www.sciencedaily.com/releases/2009/11/091130121445.htm
Thomas Jefferson University. "New mechanism of blocking HIV-1 from entering cells identified." ScienceDaily. www.sciencedaily.com/releases/2009/11/091130121445.htm (accessed October 20, 2014).

Share This



More Health & Medicine News

Monday, October 20, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Microneedle Patch Promises Painless Pricks

Microneedle Patch Promises Painless Pricks

Reuters - Innovations Video Online (Oct. 18, 2014) Researchers at The National University of Singapore have invented a new microneedle patch that could offer a faster and less painful delivery of drugs such as insulin and painkillers. Video provided by Reuters
Powered by NewsLook.com
Raw: Nurse Nina Pham Arrives in Maryland

Raw: Nurse Nina Pham Arrives in Maryland

AP (Oct. 17, 2014) The first nurse to be diagnosed with Ebola at a Dallas hospital walked down the stairs of an executive jet into an ambulance at an airport in Frederick, Maryland, on Thursday. Pham will be treated at the National Institutes of Health. (Oct. 16) Video provided by AP
Powered by NewsLook.com
Raw: Cruise Ship Returns to US Over Ebola Fears

Raw: Cruise Ship Returns to US Over Ebola Fears

AP (Oct. 17, 2014) A Caribbean cruise ship carrying a Dallas health care worker who is being monitored for signs of the Ebola virus is heading back to Texas, US, after being refused permission to dock in Cozumel, Mexico. (Oct. 17) Video provided by AP
Powered by NewsLook.com
Spanish Govt: Four Suspected Ebola Cases in Spain Test Negative

Spanish Govt: Four Suspected Ebola Cases in Spain Test Negative

AFP (Oct. 17, 2014) All four suspected Ebola cases admitted to hospitals in Spain on Thursday have tested negative for the deadly virus in a first round of tests, the government said Friday. Duration: 00:55 Video provided by AFP
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:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

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