Gold Nanoparticles in HIV Drug Delivery System

In a study, researchers believe that gold nanoparticles may breathe new life into once-promising drug candidates, in particular a compound designed to stop the spread of HIV (human immunodeficiency virus) that was shelved because of side effects. The compound TAK-779 was first proposed by researchers in 1996 and proved effective at blocking the virus from infiltrating body's immune system. But it was scuttled by 2005, because recipients suffered severe irritation at injection sites and oral doses were ineffective.

Researchers have known for years that ammonium salt molecules in the compound triggered the bad reaction. But they could not find a benign replacement able to perform its function of binding the drug to T cells, white blood cells that fight infection including HIV.

Given TAK-779's success, however, Christian Melander, an assistant professor of chemistry at North Carolina State University in Raleigh, says scientists continued to search for a substitute, which they may finally have found.

Melander and colleagues David Margolis, a professor of infectious disease at the University of North Carolina at Chapel Hill, and Daniel Feldheim, an associate professor of analytical and materials chemistry at the University of Colorado at Boulder, reported online in the Journal of the American Chemical Society that gold nanoparticles may be the answer.

Scientists have already established that microscopic particles including gold and silver can help ferry chemical compounds from one place to another in lab tests. Massachusetts Institute of Technology (M.I.T.) engineers since 2004 have been studying the potential of gold nanoparticles (coated with alternating bands of two different kinds of molecules) in particular to penetrate the protective membranes around cells without damaging them.

But, whereas the M.I.T. scientists are using nanoparticles simply as an agent to assist drug delivery, Melander and his team want nanoparticles to also be an integral part of the drug itself. Melander says the key was to determine whether gold nanoparticles would, like the ammonium salt, latch onto receptors (protein molecules embedded in a cell's membrane) on the outside of T cells to shield them from HIV.
Researchers found during lab tests that attaching 12 molecules of TAK-779 modified to exclude ammonium salt molecules to one gold nanoparticle restored the drug's ability to prevent HIV infection.

The size of the gold particles two nanometers (two billionths of a meter) in diameter is comparable to that of the HIV proteins they are trying to block. This should make them well suited to stop viral proteins from coming in contact with key receptors, says Joseph Wedekind, an associate professor of biochemistry and biophysics in the University of Rochester School of Medicine and Dentistry.

The problem is that HIV targets different receptors on T-cells and researchers only tested their compound on one of them. Another potential hitch is HIV's ability to mutate, and thereby become resistant to treatments over time, Melander says.

He notes that the next step will be to do a long-term study on whether HIV could change, eventually rendering the new compound impotent. Melander and his colleagues are also probing whether gold nanoparticles can be used to deliver an anti-HIV medicine directly to the human brain, where HIV is known to hide, replicate and mutate.

Source: https://www.scientificamerican.com/article/gold-nanoparticles-hiv/

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Nanomedicine to Eradicate HIV

In a significant breakthrough that could hasten an eventual HIV cure, a research team at the University of Nebraska Medical Center has changed the chemical structure of an existing antiviral drug to facilitate it in reaching cells and tissues where HIV resides.

Using a physiochemical scheme that alters the properties of the drug dolutegravir, UNMC scientists took the modified drug and placed it into nanocrystals. The produced drug crystals easily distributed throughout the body to tissue reservoirs of HIV infection.

The advanced drug scheme extended the life of the drug and its entry into "hidden body compartments" from the muscle site of injection while increasing its action in reducing viral growth. The tissues included the lymph nodes, the bone marrow, the intestine and the spleen.

The modified drug crystals were not toxic, did not break apart with temperature changes and were stable for months of time. All organs and bodily functions remained intact after treatment.

Coated with parts of fat, the crystals efficiently maneuvered through cell protective membranes and were stored inside cells for weeks said Howard Gendelman, M.D., professor and chair, who with Benson Edagwa, Ph.D., assistant professor, co-led the study in UNMC's Department of Pharmacology and Experimental Neuroscience (PEN).

Once stored inside cells called macrophages, the drug was slowly released from the crystal in an altered inactive form called a "prodrug." The cell then breaks the prodrug into an active drug, and the active drug is then released into the circulation from the cell and tissue stores.

"The strength of this system is that it not only can be effective in improving HIV care and prevention," said, Dr. Edagwa, who designed the drug chemical modifications, "but can be applied to many classes of drugs beyond HIV, such as drugs used to treat cancer, other infectious diseases and degenerative diseases that affect the brain."

Importantly, Dr. Gendelman said, "the new products can optimize HIV restrictive growth so that strategies that may eradicate viral infection would be successful."

UNMC has embraced the project, Dr. Gendelman said, with plans to soon complete a nanomedicine production plant that will enable the drugs and others like it to be produced on campus beginning this fall. Located on the 11th floor of The Lied Transplant Center, the plant will be a good manufacturing facility with an operating function similar to many pharmaceutical companies.

Patents have been filed and supported both by UNeMed, UNMC's technology transfer partner, and ViiV Healthcare, a subsidiary of GSK (GlaxoSmithKline). The research was funded by ViiV Healthcare and by research grants from four institutes of the National Institutes of Health -- Drug Abuse, Mental Health, Neurological Disorders and Stroke, and Aging.

Source: https://www.sciencedaily.com/releases/2018/02/180207102845.htm

New anti-viral nanoparticles that destroy broad spectrum of viruses including ‘HIV’

Viral infections kill millions of people worldwide every year, but currently available antiviral drugs are limited in that they mostly act against one or a small handful of related viruses. A few broad-spectrum drugs that prevent viral entry into healthy cells exist, but they usually need to be taken continuously to prevent infection, and resistance through viral mutation is a serious risk.

Now, an international group of researchers including UIC professor of chemistry Petr Kral, have designed new anti-viral nanoparticles that bind to a range of viruses, including herpes simplex virus, human papillomavirus, respiratory syncytial virus and Dengue and Lentiviruses. Unlike other broad-spectrum antivirals, which simply prevent viruses from infecting cells, the new nanoparticles destroy viruses.

The new nanoparticles mimic a cell surface protein called heparin sulfate proteoglycan (HSPG). A significant portion of viruses, including HIV, enter and infect healthy cells by first binding to HSPGs on the cell surface. Existing drugs that mimic HSPG bind to the virus and prevent it from binding to cells, but the strength of the bond is relatively weak. These drugs also can’t destroy viruses, and the viruses can become reactivated when the drug concentration is decreased.

Kral and his colleagues, including Lela Vukovic, assistant professor of chemistry at the University of Texas at El Paso and an author on the paper, sought to design a new anti-viral nanoparticle based on HSPG, but one that would bind more tightly to viral particles and destroy them at the same time.

“We knew the general composition of the HSPG-binding viral domains the nanoparticles should bind to, and the structures of the nanoparticles, but we did not understand why different nanoparticles behave so differently in terms of both binding strength and preventing viral entry into cells,” said Kral.

Through elaborate simulations, Kral and colleagues helped solve these issues and guided the experimentalists in tweaking the nanoparticle design so that they worked better.

The researchers used advanced computational modeling techniques to generate precise structures of various target viruses and nanoparticles down to the location of each atom. A deep understanding of the interactions between individual groups of atoms within the viruses and nanoparticles allowed the researchers to estimate the strength and permanence of potential bonds that could form between the two entities, and helped them to predict how the bond could change over time and eventually destroy the virus.

The team’s final “draft” of the anti-viral nanoparticle could bind irreversibly to a range of viruses, and caused lethal deformations to the viruses, but had no effect on healthy tissues or cells. In vitro experiments with the nanoparticles showed that they bound irreversibly to the herpes simplex virus, human papillomavirus, syncytial virus, Dengue virus and Lentivirus.

“We were able to provide the data needed to the design team so that they could develop a prototype of what we hope will be a very effective and safe broad-spectrum anti-viral that can be used to save lives,” said Kral.

Source: https://www.sciencedaily.com/releases/2017/12/171218154928.htm

Early ART treatment tied to HIV remission

The research on early antiretroviral therapy has led to the fact that treatment of the virus during infancy may suppress HIV to undetectable levels which could reduce the need for life-long drug therapy. In the study, before treatment, the child’s levels of HIV in the blood, or viral load, were very high. At around 9 weeks of age, the child started ART, which suppressed the virus to undetectable levels. The child’s treatment was halted at 40 weeks, and their immune health was monitored during years of follow-up examinations.

Investigators assessed the child’s immune health and the presence of HIV at age 9.5 years. They found a reservoir of virus in a tiny portion of immune cells, but otherwise no evidence of HIV infection was detected and there were no associated symptoms.

While the researchers detected a trace of response by the immune system, they were unable to identify any HIV capable of replicating. It was confirmed that the child does not have genetic characteristics connected with spontaneous HIV control, which suggests that the 40 weeks of ART received during infancy may have played a key role in achieving HIV remission.

Since the initial treatment, the child has maintained undetectable levels of HIV. “To our knowledge, this is the first reported case of sustained control of HIV in a child enrolled in a randomized trial of ART interruption following treatment early in infancy,” says Dr. Avy Violari, head of pediatric research at the Perinatal HIV Research Unit at the University of the Witwatersrand in Johannesburg, South Africa, co-led the study with Mark Cotton, head of the Division of Pediatric Infectious Diseases at Stellenbosch University, also in South Africa.

Source: https://www.medicalnewstoday.com/articles/318636.php