A Molecularly Engineered Lectin for Use as a Treatment for Ebola and Marburg Viruses
Abstract
Filoviruses, such as Ebola virus, are among the deadliest of human pathogens, with fatality rates reaching as high as 90% in some outbreaks and significant potential to be weaponized for use in biological warfare or in terrorist attacks. In addition, the very recent, ongoing, naturally occurring outbreak has caused considerable mortality in West Africa, and disruption and fear in the United States. Thus, development of medications that can prevent infection, or treat warfighters who become infected by filoviruses, is a high priority for the national defense and we have developed an agent that shows promise in this regard. We have cloned a lectin (sugar-binding protein) from bananas, termed BanLec, and can now easily produce large amounts of it in bacteria. The lectin binds to the high-mannose residues (sugars) on the surface of important pathogenic viruses and, as these viral sugars are necessary for the virus to enter human cells, blocks viral entry and hence infection. Most importantly, we have modified this sugar-binding protein so that it is still a highly potent anti-viral agent but loses essentially all of its mitogenic, i.e., pro-inflammatory, activity. This improvement is crucial, as unwanted inflammation might well harm the recipient of the medication. The modified BanLec is thus potentially much safer to administer to warfighters in the field. We have found that the cloned, modified molecule, termed H84T BanLec because the histidine amino acid (amino acids are the building blocks of proteins) at position 84 has been changed to a threonine amino acid, is very effective when tested in cells growing in the laboratory against influenza, SARS, MERS, HIV, and hepatitis C virus at nanomolar (very low) concentrations, and studies in mice have demonstrated efficacy against influenza, HIV, and hepatitis C virus. More recently, we have found H84T BanLec to be active against Ebola in the laboratory. Therefore, in the first year of the proposal we will further examine whether H84T BanLec can serve as a therapeutic agent for infection with Ebola using naturally-occurring Ebola virus in tissue culture (cells growing in the laboratory) and mouse experiments. We will also study the pharmacodynamics (distribution, elimination, toxicity) of the drug. In subsequent years of the proposal, we will address optimal dosing. In addition, as it is important to confirm efficacy of an antiviral agent in more than one animal model, H84T BanLec will also be tested against Ebola virus in a guinea pig model. We will also assess whether the lectin can be used against the related and deadly Marburg virus. Further, the molecular level mechanisms of action of this newly-engineered anti-filovirus lectin will be explored in detail, leading to improved therapy. Use of H84 T BanLec, either alone or in conjunction with other agents, shows promise for protecting and/or treating warfighters exposed to Ebola and related viruses and, as such, its development supports the national defense effort and protects the lives of warfighters.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- May 26, 2016
- Source ID
- HDTRA11510067
Entities
People
- David M Markovitz
Organizations
- Defense Threat Reduction Agency
- University of Michigan