NEW YORK (Dec. 19, 2007) -- Two deadly and highly infectious viruses -- both potential bioterror threats -- may have met their match in a new drug developed by scientists at Weill Cornell Medical College in New York City.
Hendra and Nipah viruses are related, newly recognized zoonotic viruses that can spread from their natural reservoir in fruit bats to larger animals -- including pigs, horses and humans.
The mode of transmission isn't clear, but is thought to be relatively easy -- either by close contact with an infected host or by breathing in the microscopic pathogens. Infection often leads to a fatal encephalitis, and there is currently no effective treatment against these illnesses.
However, in breakthrough research conducted last year, researchers at Weill Cornell manipulated a peptide (protein) related to a third pathogen, parainfluenza virus, that appeared to block "pseudo" Hendra and Nipah viruses from entering and infecting human cells.
Now, this "entry inhibitor" approach has proven effective in blocking the infection of live virus in animal cells, pointing the way to a drug that could be stockpiled to help stop an outbreak in humans.
Those findings appeared recently in the Journal of Virology.
"We have now tested the peptide-based entry inhibitor in monkey cells to show that it does effectively block infection with both live Hendra and Nipah," explains study senior researcher Dr. Anne Moscona, a professor of pediatrics and of microbiology and immunology at Weill Cornell Medical College, and an attending physician at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.
Public health officials have sounded alarm bells ever since Nipah virus first emerged in pigs and then humans living in Southeast Asia. More recently, cases of Hendra virus began to show up in horses and their human handlers in Australia.
Experts who drew up the U.S. National Institute of Allergy and Infectious Diseases' Biodefense Research Agenda have included both viruses as potential bioterror agents.
"Theoretically, it's possible to go out into the field and collect Hendra virus from bats, for example," Dr. Moscona says. "We've been urgently working on this because right now there's absolutely nothing that can be done to stop this fatal, transmissible illness."
Luckily, prior research at Weill Cornell had laid out some important groundwork. The study's lead author, Dr. Matteo Porotto, has worked for years studying these types of microorganisms, using the parainfluenza virus as his model.
"We were able to develop the strategy that we describe in this paper because our work on parainfluenza had already helped us understand how these viruses fuse with host cells," says Dr. Porotto, assistant professor of microbiology in the Department of Pediatrics at Weill Cornell Medical College.
Based on that work, Drs. Porotto and Moscona knew that when the receptor-binding molecule on the virus -- simply called "G" -- binds to the surface of the cell, it activates a special "fusion protein." This fusion molecule has to then undergo some shape changes to turn itself into a six-helix bundle. Once that's done, it helps the virus fuse with, and enter, the cell, Dr. Porotto explains.
However, the Weill Cornell team discovered that a peptide specific to the parainfluenza virus "fusion protein" ("F") can inhibit this shape-changing step -- stopping fusion cold.
"Surprisingly, this parainfluenza F-peptide turned out to be even more effective at inhibiting Hendra virus fusion than peptides derived from the Hendra virus itself," Dr. Moscona says. "It also appears to do much the same thing with the Nipah virus, inhibiting fusion there, too."
The team discovered just why the F peptide works so well in a collaboration with Dr. Min Lu, associate professor of biochemistry at Weill Cornell. "These peptides act like door jambs -- their particular shapes prevent 'doors' in the viral 'fusion protein' from closing as they should. The parainfluenza peptide's shape simply makes it a better door jamb," Dr. Porotto said.
Much of this research is modeled on insights gained from two decades of investigation into another lethal virus, HIV. In fact, T-20, or Fuzeon -- one of the earliest effective HIV-suppressing drugs -- acts on a similar principle to block that virus' entry into cells.
The next step, according to the researchers, is to use what they've learned to design even more effective peptides that should work even better.
"However, one issue with peptides is that you have to be concerned about how long they are going to last in the bloodstream," Dr. Moscona says. "So, we are also developing methods of sustained-release -- for example, encasing the peptide in a polymer pellet that would be injected under the skin. The pellet would then release the drug slowly over the course of a week. That could form a viable method suitable for stockpiling," she says.
This research was supported by a Public Health Service grant from the U.S. National Institutes of Health's NorthEast Center of Excellence for Biodefense and Emerging Infections Disease Research.
Collaborators included Paolo Carta and Dr. Yiqun Deng of Weill Cornell Medical College in New York City; Dr. Michael Whitt, of the University of Tennessee Health Science Center, Memphis; Glenn E. Kellogg, of Virginia Commonwealth University in Richmond, Va.; and Dr. Bruce Mungall, of the Australian Animal Health Laboratory, CSIRO Livestock Industries, Geelong, Australia.
Weill Cornell Medical College
Weill Cornell Medical College -- Cornell University's Medical School located in New York City -- is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Weill Cornell, which is a principal academic affiliate of NewYork-Presbyterian Hospital, offers an innovative curriculum that integrates the teaching of basic and clinical sciences, problem-based learning, office-based preceptorships, and primary care and doctoring courses. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research in such areas as stem cells, genetics and gene therapy, geriatrics, neuroscience, structural biology, cardiovascular medicine, infectious disease, obesity, cancer, psychiatry and public health -- and continue to delve ever deeper into the molecular basis of disease in an effort to unlock the mysteries behind the human body and the malfunctions that result in serious medical disorders. The Medical College -- in its commitment to global health and education -- has a strong presence in such places as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. With the historic Weill Cornell Medical College in Qatar, the Medical School is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -- from the development of the Pap test for cervical cancer to the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial for gene therapy for Parkinson's disease, the first indication of bone marrow's critical role in tumor growth, and, most recently, the world's first successful use of deep brain stimulation to treat a minimally-conscious brain-injured patient. For more information, visit www.med.cornell.edu.
Journal
Journal of Virology