Francesco Stellacci, EPFL, Switzerland
Supramolecular Approaches for Novel Antiviral Therapy
Written by Xun Gong
Viruses are a class of lethal communicable diseases that can have profound impact on the global population. For example, the impact of the first and second world wars is dwarfed by that of the Spanish flu. Treatment of viruses can be divided into prevention and post infection treatment. These treatments can be further divided into three categories:
Antivirals: Approved medication that prevents intracellular viral replication. They work by targeting cell components. Because cellular components do not amplify, the treatment intensity is known.
Virucidal: Drugs that kill viruses. The problem is that these drugs that kill viruses are also cytotoxic. We also need to play the number game based on viral replication number.
Viralstatic: Prevent viral entry to the cell. However, because binding is reversible, dilution would result in reactivation of viral particles. There has been failed clinical trials in this area.
One such example of viralstatic agents is heparin sulfate proteoglycans. Their ability to bind is very conserved between viral types. The Stellacci group first attached sulfate groups to nanoparticles and found that these particles behave viral statically. The binding regions of the virus usually have multiple sites for interaction (5 in the case of papilloma). It is hypothesized that binding multiple regions can create a 100 pN force that can trigger premature viral unpacking, and thus particle destruction. Testing with GFP HIV particles show concentration-dependent decrease of infectability.
Testing wildtype viruses—HSV1, HSV2, HPV—shows the same result, with only sulfate group linker length serving as an important modulatory factor. Through dilution testing, it was shown that the virucidal effect is not dilution-dependent and not reversible. In a culture system, this treatment is shown to be effective for HSV2-infected vaginal tissue. The proposed mechanism from imaging is mechanical bulging of the viral coat causing it to expel the capsid.
Lastly, nanoparticles are not necessary. Cyclodextran with sulfate groups attached with the correct linker length has proven to be equally effective. Animal experiments show mice were cured of respiratory viral infections by spraying 10 ug of drug once in the nose. Scaled up, this would mean 2.5 mg for a 60 kg human.