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Ebola virus reproduction in laboratory-grown cells is severely hampered by enzyme-inhibiting chemicals, and these chemicals deserve further study as possible treatments for Ebola virus infections in humans, report scientists supported in part by the National Institute of Allergy and Infectious Diseases (NIAID), a component of the National Institutes of Health (NIH).
The researchers, whose paper is published online in Science Express, identified two cellular enzymes Ebola virus must have to reproduce. When those enzymes are blocked, the virus loses most of its infectivity, the scientists found.
Ebola virus, like the Marburg virus now alarming Angola, is a filovirus, a family of viruses that cause severe and frequently fatal hemorrhagic fevers. Finding medical countermeasures for viral hemorrhagic fevers is a global public health priority because not only do these diseases occur naturally, but they also have the potential to be unleashed by bioterrorists, says NIH director Elias A. Zerhouni, MD.
This new research sheds light on the mechanism Ebola virus uses to enter cells, notes NIAID director Anthony S. Fauci, MD. These findings raise the possibility of a broad-spectrum antiviral therapy that could be effective against multiple hemorrhagic fever viruses.
Senior author James M. Cunningham, MD, of Brigham and Womens Hospital and Harvard Medical School in Boston, and his colleagues discovered two cellular enzymes that the Ebola virus co-opts and uses to cut up one of the virus surface proteins. Once this protein is snipped apart, the virus is free to begin multiplying. The scientists applied broad-spectrum enzyme inhibitors to mammalian cells before exposing them to Ebola virus. When one specific cellular enzyme, cathepsin B, was inhibited, the infectivity of Ebola virus dropped to near zero. An accessory role is played by another cellular enzyme, cathepsin L, the scientists determined.
Inhibitors of cathepsins are already under clinical development as anti-cancer drugs. The authors write, Further investigation of the antiviral efficacy of [enzyme] inhibitors may be warranted. The wealth of existing knowledge regarding the design and in vivo pharmacology of these inhibitors may facilitate development of an anti-Ebola-virus therapy.
The work was done in collaboration with Nancy J. Sullivan, PhD, of NIAIDs Vaccine Research Center.
The papers lead author, Kartik Chandran, PhD, of Brigham and Womens Hospital and Harvard Medical School, is supported by a career development award from the NIAID Regional Centers of Excellence for Biodefense and Emerging Infectious Diseases Research (RCE) program. In 2003, NIAID funded the establishment of eight RCEs nationwide. The RCE program supports interdisciplinary research aimed at new and improved therapies, vaccines, diagnostics and other tools to protect against the threat of bioterrorism and other emerging and re-emerging diseases.
NIAID is a component of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on transplantation and immune-related illnesses, including autoimmune disorders, asthma and allergies.
Reference: K Chandran et al. "Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection". Science Express. Published online April 14, 2005. DOI: 10.1126/science.1110656.