A team of scientists, including University of Illinois–Champagne Urbana chemistry professor Petr Král, Ph.D., says it has designed new antiviral nanoparticles that bind to a range of viruses, including herpes simplex virus, human papillomavirus, respiratory syncytial virus, dengue virus, and lentiviruses. Unlike other broad-spectrum antivirals, which simply prevent viruses from infecting cells, the new nanoparticles destroy viruses, note the researchers who published their study (“Broad-Spectrum Non-Toxic Antiviral Nanoparticles with a Virucidal Inhibition Mechanism”) in Nature Materials.
“Viral infections kill millions yearly. Available antiviral drugs are virus-specific and active against a limited panel of human pathogens. There are broad-spectrum substances that prevent the first step of virus–cell interaction by mimicking heparan sulfate proteoglycans (HSPG), the highly conserved target of viral attachment ligands (VALs). The reversible binding mechanism prevents their use as a drug, because, upon dilution, the inhibition is lost. Known VALs are made of closely packed repeating units, but the aforementioned substances are able to bind only a few of them,” wrote the investigators.
“We designed antiviral nanoparticles with long and flexible linkers mimicking HSPG, allowing for effective viral association with a binding that we simulate to be strong and multivalent to the VAL repeating units, generating forces (∼190 pN) that eventually lead to irreversible viral deformation. Virucidal assays, electron microscopy images, and molecular dynamics simulations support the proposed mechanism. These particles show no cytotoxicity, and in vitro nanomolar irreversible activity against herpes simplex virus (HSV), human papilloma virus, respiratory syncytial virus (RSV), dengue and lenti virus. They are active ex vivo in human cervicovaginal histocultures infected by HSV-2 and in vivo in mice infected with RSV.”
A significant portion of viruses, including human immunodeficiency virus (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.
Dr. Král and his colleagues, including Lela Vukovic, Ph.D., assistant professor of chemistry at the University of Texas at El Paso and an author on the paper, wanted to develop a new antiviral nanoparticle based on HSPG, but one that would bind more tightly to viral particles and destroy them at the same time. Drs. Král’s and Vukovic's groups worked with experimentalists, virus experts, and biochemists from Switzerland, Italy, France, and the Czech Republic.
“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 Dr. Král.
The researchers used simulations and advanced computational modeling techniques to generate precise structures of various target viruses and nanoparticles down to the location of each atom. The team was able 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 final “draft” of the antiviral 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 antiviral that can be used to save lives,” said Dr. Král.