Fort Belvoir, Va. - Scientists are seeking to conquer deadly viral threats by using engineered proteins, leading to better protections for warfighters from some of the most dangerous threats they face, including plague and Ebola.
Researchers funded by the Defense Threat Reduction Agency’s Joint Science and Technology Office are working to develop new antiviral countermeasures for the warfighter, utilizing the influenza virus. Historically influenza changes its molecular structure rapidly, which makes developing an effective vaccine challenging. While researchers chose to work with the influenza virus, this computational protein design could have broad-spectrum applicability to several viral threats.
New progress in computational protein design demonstrates its vital application in a wide array of countermeasures. Recently published in PLOS Pathogens “A Computationally Designed Hemagglutinin Stem-Binding Protein Provides In Vivo Protection from Influenza Independent of a Host Immune Response,” scientists report that a computationally designed protein was able to protect against the influenza virus in an animal model.
This JSTO effort is managed by Dr. Ilya Elashvili and led by Dr. David Baker of University of Washington. Dr. Baker’s research identifies a small (<100 amino acid) engineered protein that was able to protect mice against diverse influenza virus strains.
As a starting point, the researchers used previously reported computationally designed proteins that showed high affinity and broad specificity towards diverse influenza virus strains. Both studies were previously published in the journals Science and Nature Biotechnology.
In the current work, Dr. Baker optimized the protein by mutational and selection strategies in order to further improve its neutralizing potency for broad viral influenza strains. The resultant protein was found to be an effective antiviral and protected mice against lethal challenge from diverse influenza virus strains when administered as a prophylactic or therapeutic in vivo.
A single intranasal dose of protein (6 mg/kg) prevented viral infection in mice, when administered up to 48 hours before lethal viral challenge. If administered closer to the viral contact (two hours prior), the dosing amounts could be significantly reduced to 0.1 mg/kg.
In the absence of prophylactic treatment, the protein provided complete protection from disease when administered as a single dose (3 mg/kg) two hours after challenge or if administered as a daily therapeutic treatment for four days (once per day) after the challenge.
Importantly, one day post-challenge, a single intranasal dose of the protein substantially outperformed ten oral doses of the leading influenza antiviral, Tamiflu, administered twice daily for five days. The protein was able to provide this protection by binding to a critical part of the viral protein without involving the host’s antiviral immune response that is generally invoked by antibodies.
These studies demonstrate the potential of computationally designed binding proteins as a new class of antivirals for prophylactics and therapeutics to protect warfighters from natural or manmade viral threats.
POC: Dr. Ilya Elashvili; ilya.elashvili.civ@mail.mil