Bioprospecting for Antiviral Peptides
Abstract
Science predicts that as the climate changes, northern latitudes will become warmer, facilitating the spread of viruses that are transmitted by mosquitoes, referred to as arboviruses, which were previously limited to tropical and subtropical regions. In addition, we have seen the rapid, worldwide spread of specific mosquito transmitted viruses as a consequence of globalization. Arboviruses are of particular concern because many of these are known to cause severe acute human disease, and some have been previously weaponized. Two families of arboviruses, Flaviviruses (e.g., Zika virus and West Nile virus) and Alphaviruses (e.g., chikungunya virus and Venezuelan equine encephalitis virus or VEEV), are of particular interest due to their ability to cause significant human disease. Here we focus on the study of VEEV, which can cause fatal encephalitis, as a model arbovirus. Importantly, no Food and Drug Administration-approved vaccines or therapeutic agents are currently available for almost all arboviruses. It is in the interests of national security and public health to develop effective treatments options for this class of pathogens. We have been studying the potential of peptides known as cationic antimicrobial peptides (CAMPs) as resources for developing new antimicrobial therapeutics. These peptides are naturally produced as part of the immune response in reptiles, humans, and even mosquitoes. There is evidence that indicates that reptiles produce these peptides as a way to fight off arboviruses. We have developed a novel method using microparticles to capture low levels of CAMPs from the plasma of reptiles (American alligator and Komodo dragon plasma). Once the particles preferentially bind to CAMPs, the particle/CAMP complexes can be removed from the plasma, which allows enrichment and facilitates identification of these peptides. Due to technical limitations, analysis of plasma without the particle enrichment step would be challenging and result in few to no low abundance CAMPs being identified. CAMPs that we identified from the American alligator and Komodo dragon have shown antimicrobial activity against multiple bacterial pathogens; however, they were not selected or tested for their ability to inhibit viruses. We hypothesize that large-scale analysis of the peptides produced in response to arbovirus exposure in reptiles will reveal valuable insights into their ability to resist or tolerate important human viral pathogens and result in the identification of novel therapeutics to protect the Warfighter from these pathogens. To address this hypothesis, we will first develop two new classes of hydrogel particles for the purpose of differentially enriching peptides that target VEEV, as opposed to those that would target human cells. By doing so, we will eliminate any potential toxicity of these peptides and identify peptides that are selective for viral components. We will then use these particles to capture antiviral host-defense peptides produced by reptile (alligator and snake) blood cells in response to exposure to VEEV. Harvests will be analyzed to determine the identity of the captured peptides. Candidate antiviral peptides will be chemically synthesized and evaluated for their ability to prevent or inhibit the ability of VEEV to replicate/grow. This approach is expected to identify novel peptides that can be used for the treatment of VEEV infection and potentially other arboviruses of concern.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810801
Entities
People
- Barney M Bishop
Organizations
- George Mason University
- United States Army