Tag Archives: glycoprotein

Nano-decoy for human influenza A virus

Leave a reply

While the implications for this research are exciting, keep in mind that so far they’ve been testing immune-compromised mice. An Oct. 24, 2016 news item on Nanowerk announces the research,

To infect its victims, influenza A heads for the lungs, where it latches onto sialic acid on the surface of cells. So researchers created the perfect decoy: A carefully constructed spherical nanoparticle coated in sialic acid lures the influenza A virus to its doom. When misted into the lungs, the nanoparticle traps influenza A, holding it until the virus self-destructs.

An Oct. 24, 2015 Rensselaer Polytechnic Institute press release by Mary L. Martialay, which originated the news item, describes the research (Note: Links have been removed),

In a study on immune-compromised mice, the treatment reduced influenza A mortality from 100 percent to 25 percent over 14 days. The novel approach, which is radically different from existing influenza A vaccines, and treatments based on neuraminidase inhibitors, could be extended to a host of viruses that use a similar approach to infecting humans, such as Zika, HIV, and malaria. …

“Instead of blocking the virus, we mimicked its target – it’s a completely novel approach,” said Robert Linhardt, a glycoprotein expert and Rensselaer Polytechnic Institute professor who led the research. “It is effective with influenza and we have reason to believe it will function with many other viruses. This could be a therapeutic in cases where vaccine is not an option, such as exposure to an unanticipated strain, or with immune-compromised patients.”

The project is a collaboration between researchers within the Center for Biotechnology and Interdisciplinary Studies (CBIS) at Rensselaer and several institutions in South Korea including Kyungpook National University. Lead author Seok-Joon Kwon, a CBIS research scientist, coordinated the project across borders, enabling the South Korean institutions to test a drug designed and characterized at Rensselaer. …

To access the interior of a cell and replicate itself, influenza A must first bind to the cell surface, and then cut itself free. It binds with the protein hemagglutinin, and severs that tie with the enzyme neuraminidase. Influenza A produces numerous variations each of hemagglutinin and neuraminidase, all of which are antigens within the pathogen that provoke an immune system response. Strains of influenza A are characterized according to the variation of hemagglutinin and neuraminidase they carry, thus the origin of the familiar H1N1 or H3N2 designations.

Medications to counter the virus do exist, but all are vulnerable to the continual antigenic evolution of the virus. A yearly vaccine is effective only if it matches the strain of virus that infects the body. And the virus has shown an ability to develop resistance to a class of therapeutics based on neuraminidase inhibitors, which bind to and block neuraminidase.

The new solution targets an aspect of infection that does not change: all hemagglutinin varieties of influenza A must bind to human sialic acid. To trap the virus, the team designed a dendrimer, a spherical nanoparticle with treelike branches emanating from its core. On the outermost branches, they attached molecules, or “ligands,” of sialic acid.

The research found that the size of the dendrimer and the spacing between the ligands is integral to the function of the nanoparticle. Hemagglutinin occurs in clusters of three, or “trimers,” on the surface of the virus, and researchers found that a spacing of 3 nanometers between ligands resulted in the strongest binding to the trimers. Once bound to the densely packed dendrimer, viral neuraminidase is unable to sever the link. The coat of the virus contains millions of trimers, but the research revealed that only a few links provokes the virus to discharge its genetic cargo and ultimately self-destruct.

A different approach, using a less structured nanoparticle, had been previously tested in unrelated research, but the nanoparticle selected proved both toxic, and could be inactivated by neuraminidase. The new approach is far more promising.

“The major accomplishment was in designing an architecture that is optimized to bind so tightly to the hemagglutinin, the neuraminidase can’t squeeze in and free the virus,” said Linhardt. “It’s trapped.”

Here’s a link to and a citation for the paper,

Nanostructured glycan architecture is important in the inhibition of influenza A virus infection by Seok-Joon Kwon, Dong Hee Na, Jong Hwan Kwak, Marc Douaisi, Fuming Zhang, Eun Ji Park, Jong-Hwan Park, Hana Youn, Chang-Seon Song, Ravi S. Kane, Jonathan S. Dordick, Kyung Bok Lee, & Robert J. Linhardt. Nature Nanotechnology (2016)  doi:10.1038/nnano.2016.181 Published online 24 October 2016

This paper is behind a paywall.

Nanoparticles could make blood clot faster

Leave a reply

It was the 252nd meeting for the American Chemical Society from Aug. 21 – 25, 2016 and that meant a flurry of news about the latest research. From an Aug. 23, 2016 news item on Nanowerk,

Whether severe trauma occurs on the battlefield or the highway, saving lives often comes down to stopping the bleeding as quickly as possible. Many methods for controlling external bleeding exist, but at this point, only surgery can halt blood loss inside the body from injury to internal organs. Now, researchers have developed nanoparticles that congregate wherever injury occurs in the body to help it form blood clots, and they’ve validated these particles in test tubes and in vivo [animal testing].

The researchers will present their work today [Aug. 22, 2016] at the 252nd National Meeting & Exposition of the American Chemical Society (ACS). ACS, the world’s largest scientific society, is holding the meeting here through Thursday. It features more than 9,000 presentations on a wide range of science topics.

An Aug. 22, 2016 American Chemical Society (ACS) news release (also on EurekAlert), which originated the news item, provided more detail,

“When you have uncontrolled internal bleeding, that’s when these particles could really make a difference,” says Erin B. Lavik, Sc.D. “Compared to injuries that aren’t treated with the nanoparticles, we can cut bleeding time in half and reduce total blood loss.”

Trauma remains a top killer of children and younger adults, and doctors have few options for treating internal bleeding. To address this great need, Lavik’s team developed a nanoparticle that acts as a bridge, binding to activated platelets and helping them join together to form clots. To do this, the nanoparticle is decorated with a molecule that sticks to a glycoprotein found only on the activated platelets.

Initial studies suggested that the nanoparticles, delivered intravenously, helped keep rodents from bleeding out due to brain and spinal injury, Lavik says. But, she acknowledges, there was still one key question: “If you are a rodent, we can save your life, but will it be safe for humans?”

As a step toward assessing whether their approach would be safe in humans, they tested the immune response toward the particles in pig’s blood. If a treatment triggers an immune response, it would indicate that the body is mounting a defense against the nanoparticle and that side effects are likely. The team added their nanoparticles to pig’s blood and watched for an uptick in complement, a key indicator of immune activation. The particles triggered complement in this experiment, so the researchers set out to engineer around the problem.

“We made a battery of particles with different charges and tested to see which ones didn’t have this immune-response effect,” Lavik explains. “The best ones had a neutral charge.” But neutral nanoparticles had their own problems. Without repulsive charge-charge interactions, the nanoparticles have a propensity to aggregate even before being injected. To fix this issue, the researchers tweaked their nanoparticle storage solution, adding a slippery polymer to keep the nanoparticles from sticking to each other.

Lavik also developed nanoparticles that are stable at higher temperatures, up to 50 degrees Celsius (122 degrees Fahrenheit). This would allow the particles to be stored in a hot ambulance or on a sweltering battlefield.

In future studies, the researchers will test whether the new particles activate complement in human blood. Lavik also plans to identify additional critical safety studies they can perform to move the research forward. For example, the team needs to be sure that the nanoparticles do not cause non-specific clotting, which could lead to a stroke. Lavik is hopeful though that they could develop a useful clinical product in the next five to 10 years.

It’s not unusual for scientists to give an estimate of 5 – 10 years before their science reaches the market.  Another popular range is 3 – 5 years.