Potential new treatment for deadly nipah, hendra viruses identified

[tetano]

Washington, Oct 29 (ANI): Scientists have identified a potential new treatment for the Nipah and Hendra viruses, two lethal and emerging viruses for which there is currently no treatment or vaccine available.


The finding by scientists at Weill Cornell Medical College could also lead to new treatments for measles, mumps and influenza.


The Nipah and Hendra viruses are members of the genus Henipavirus, a new class of virus in the Paramyxoviridae family, which includes the measles and the human parainfluenza virus (HPIV) that causes pediatric respiratory disease.

The henipaviruses are carried by fruit bats (flying foxes) and are capable of causing illness and death in domestic animals and humans.

"These viruses are of great concern. The Hendra virus is highly fatal and is a considered a potential agent of bioterrorism. It currently poses a serious threat to livestock in Australia, where sporadic and deadly transmission to humans has occurred, with the potential for broader dissemination," says Dr. Matteo Porotto, the study's lead author

"And the Nipah virus, which causes fatal encephalitis in up to 70 percent of human cases, causes seasonal outbreaks in Asia with person-to-person transmission now becoming a primary mode of infection. This virus could certainly cause global outbreaks," Dr. Porotto said.

Dr. Porotto and colleagues present a new strategy to prevent and treat these infections that may be broadly applicable for other "enveloped" viral pathogens, characterized by an outer wrapping that comes from the infected host cell.

The new treatment was successfully tested in an animal model demonstrating central nervous system symptoms similar to those seen in humans.

The new research appears in today's edition of the prestigious journal Public Library of Science (PLoS) Pathogens. (ANI)

http://news.oneindia.in/2010/10/29/potentialnew-treatment-for-deadly-nipah-hendravir.html

 

[tetano]

Re: Potential new treatment for deadly nipah, hendra viruses identified

Inhibition of Nipah Virus Infection In Vivo: Targeting an Early Stage of Paramyxovirus Fusion Activation during Viral Entry



Matteo Porotto1*, Barry Rockx2, Christine C. Yokoyama1, Aparna Talekar1, Ilaria DeVito1, Laura M. Palermo1, Jie Liu3, Riccardo Cortese4, Min Lu3, Heinz Feldmann2, Antonello Pessi5, Anne Moscona1*

1 Departments of Pediatrics and of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, United States of America, 2 Laboratory of Virology, Division of Intramural research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, United States of America, 3 Department of Biochemistry, Weill Medical College of Cornell University, New York, New York, United States of America, 4 CEINGE, Naples, Italy, 5 PeptiPharma, Rome, Italy
Abstract Top

In the paramyxovirus cell entry process, receptor binding triggers conformational changes in the fusion protein (F) leading to viral and cellular membrane fusion. Peptides derived from C-terminal heptad repeat (HRC) regions in F have been shown to inhibit fusion by preventing formation of the fusogenic six-helix bundle. We recently showed that the addition of a cholesterol group to HRC peptides active against Nipah virus targets these peptides to the membrane where fusion occurs, dramatically increasing their antiviral effect. In this work, we report that unlike the untagged HRC peptides, which bind to the postulated extended intermediate state bridging the viral and cell membranes, the cholesterol tagged HRC-derived peptides interact with F before the fusion peptide inserts into the target cell membrane, thus capturing an earlier stage in the F-activation process. Furthermore, we show that cholesterol tagging renders these peptides active in vivo: the cholesterol-tagged peptides cross the blood brain barrier, and effectively prevent and treat in an established animal model what would otherwise be fatal Nipah virus encephalitis. The in vivo efficacy of cholesterol-tagged peptides, and in particular their ability to penetrate the CNS, suggests that they are promising candidates for the prevention or therapy of infection by Nipah and other lethal paramyxoviruses.

http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1001168

 

[Giuseppe]

Re: Potential new treatment for deadly nipah, hendra viruses identified

Inhibition of Nipah Virus Infection In Vivo: Targeting an Early Stage of Paramyxovirus Fusion Activation during Viral Entry (PLoS, abstract, edited)

[Source: PloS Pathogens, full text: <cite cite="http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1001168?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+plospathogens%2FNewArticles+%28Ambra+-+Pathogens+New+Articles%29">PLoS Pathogens: Inhibition of Nipah Virus Infection In Vivo: Targeting an Early Stage of Paramyxovirus Fusion Activation during Viral Entry</cite>. Abstract, edited.]

Research Article

Inhibition of Nipah Virus Infection In Vivo: Targeting an Early Stage of Paramyxovirus Fusion Activation during Viral Entry

Matteo Porotto 1*, Barry Rockx 2, Christine C. Yokoyama 1, Aparna Talekar 1, Ilaria DeVito 1, Laura M. Palermo 1, Jie Liu 3, Riccardo Cortese 4, Min Lu 3, Heinz Feldmann 2, Antonello Pessi 5, Anne Moscona 1*

1 Departments of Pediatrics and of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, United States of America,
2 Laboratory of Virology, Division of Intramural research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, United States of America,
3 Department of Biochemistry, Weill Medical College of Cornell University, New York, New York, United States of America,
4 CEINGE, Naples, Italy,
5 PeptiPharma, Rome, Italy


Abstract

In the paramyxovirus cell entry process, receptor binding triggers conformational changes in the fusion protein (F) leading to viral and cellular membrane fusion. Peptides derived from C-terminal heptad repeat (HRC) regions in F have been shown to inhibit fusion by preventing formation of the fusogenic six-helix bundle. We recently showed that the addition of a cholesterol group to HRC peptides active against Nipah virus targets these peptides to the membrane where fusion occurs, dramatically increasing their antiviral effect. In this work, we report that unlike the untagged HRC peptides, which bind to the postulated extended intermediate state bridging the viral and cell membranes, the cholesterol tagged HRC-derived peptides interact with F before the fusion peptide inserts into the target cell membrane, thus capturing an earlier stage in the F-activation process. Furthermore, we show that cholesterol tagging renders these peptides active in vivo: the cholesterol- tagged peptides cross the blood brain barrier, and effectively prevent and treat in an established animal model what would otherwise be fatal Nipah virus encephalitis. The in vivo efficacy of cholesterol-tagged peptides, and in particular their ability to penetrate the CNS, suggests that they are promising candidates for the prevention or therapy of infection by Nipah and other lethal paramyxoviruses.


Author Summary

Nipah (NiV) and Hendra (HeV) viruses are two lethal emerging zoonotic paramyxoviruses. In addition to acute infection, these viruses may lead to late-onset disease or relapse of encephalitis years after initial infection, as well as persistent or delayed neurological sequelae. We present a new strategy to prevent and treat NiV/HeV infection that may be broadly applicable for enveloped viral pathogens. Enveloped viruses must fuse their membrane with the target cell membrane in order to initiate infection, and blocking this step can prevent or treat infection, as clinically validated for HIV. For paramyxoviruses, however, peptides that bind the viral fusion protein have been shown to inhibit fusion in vitro, but not in vivo. The new strategy that we present here opens the door to clinically effective paramyxovirus fusion-inhibitory peptides. By targeting fusion-inhibitory peptides to the target membrane using a cholesterol tag, we capture an early stage in the viral fusion- activation process, thus drastically enhancing the efficacy of these peptides at inhibiting viral entry. Importantly, this strategy prevents and treats lethal Nipah virus infection in vivo. Membrane targeting of antiviral peptides thus offers a new approach to development of highly effective peptide fusion antivirals against important human pathogens.


Citation:
Porotto M, Rockx B, Yokoyama CC, Talekar A, DeVito I, et al. (2010) Inhibition of Nipah Virus Infection In Vivo: Targeting an Early Stage of Paramyxovirus Fusion Activation during Viral Entry. PLoS Pathog 6(10): e1001168. doi:10.1371/journal.ppat.1001168

Editor: F?lix A. Rey, Institut Pasteur, France

Received: June 22, 2010; Accepted: September 29, 2010; Published: October 28, 2010

This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.

Funding: This work was supported by Public Health Service grants AI31971, AI076335, and AI090354 from the National Institutes of Health (NIAID) to AM, AI079771 to ML, NIH (NIAID) Northeast Center of Excellence for Bio-defense and Emerging Infectious Disease Research U54AI057158 grants to AM and MP (PI of Center of Excellence grant: W.I. Lipkin), and Division of Intramural Research (DIR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) to HF. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: Matteo Porotto and Anne Moscona comment on published articles for Faculty of 1000 (virology section).

* E-mail: Map2028@med.Cornell.edu (MP); anm2047@med.Cornell.edu (AM)

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[Emily]

Re: Potential new treatment for deadly nipah, hendra viruses identified

Here's another article about the research published in the Cornell Sun last November.

http://cornellsun.com/node/44860