Design drugs that circumvent viral drug resistance - mechanism behind Tamiflu resistance

Oseltamivir (Tamiflu) is currently the frontline antiviral drug employed to fight the flu virus in infected individuals by inhibiting neuraminidase, a flu protein responsible for the release of newly synthesized virions. However, oseltamivir resistance has become a critical problem due to rapid mutation of the flu virus. Unfortunately, how mutations actually confer drug resistance is not well understood. In this study, we employ molecular dynamics (MD) and steered molecular dynamics (SMD) simulations, as well as graphics processing unit (GPU)-accelerated electrostatic mapping, to uncover the mechanism behind point mutation induced oseltamivir-resistance in both H5N1 “avian” and H1N1pdm “swine” flu N1-subtype neuraminidases. The simulations reveal an electrostatic binding funnel that plays a key role in directing oseltamivir into and out of its binding site on N1 neuraminidase. The binding pathway for oseltamivir suggests how mutations disrupt drug binding and how new drugs may circumvent the resistance mechanisms.

Oseltamivir (Tamiflu) is the main antiviral drug used to fight viral influenza outbreaks such as the recent swine flu (H1N1pdm) global pandemic and avian (H5N1) outbreak in Asia. Oseltamivir inhibits a protein on the surface of flu viruses called neuraminidase, which is responsible for releasing newly formed viruses. The rapid emergence of drug resistance in H5N1 avian flu (and recently the H1N1pdm strain) has already motivated numerous studies to understand how mutations render oseltamivir ineffective, but no focused investigation has yet elucidated the specific mechanism behind mutation-induced drug resistance. Here, large scale computer simulations are employed to study both H5N1 and H1N1pdm neuraminidase to answer the questions: how does N1-subtype neuraminidase bind oseltamivir, and how would mutations alter this process? The key finding revealed in our simulations is the discovery of oseltamivir binding to neuraminidase by a charged pathway on the protein surface. We suggest that point mutations may disrupt drug binding by interfering with this pathway. Our results explain the fundamental mechanism behind oseltamivir resistance and pave the way for the design of drugs that circumvent viral drug resistance.

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Cell culture H1N1 vacc could be ready in 3 months

Industry response to the H1N1 pandemic suggests that cell culture vaccine production is about to come of age with two firms that use the technique, Novartis and Baxter, claiming it will cut development and manufacturing timelines by months.

Margaret Chan officially declared the pandemic explaining that H1N1 infections worldwide can no longer be traced and that “further spread is considered inevitable.” She asked drugmakers to begin preparing for large-scale H1N1 vaccine production when manufacture of seasonal stocks is completed, prompting a flurry of industry updates from vaccine producers.

Baxter and Novartis aim for early availability

The most eye-catching of these responses came from US drugmaker Baxter which announced it has completed testing of its Celvapan H1N1 vaccine and is “now in full-scale production,” and is working to deliver it as early as next month. Traditionally, seasonal influenza vaccines are mass produced using the albumin found in fertilised hens eggs as a growth media.

Swiss drug major Novartis made similar claims for its cell culture developed vaccine, although it was more measured about its timelines.

Novartis said it completed making the first batch of a H1N1 vaccine weeks ahead of expectations, explaining that its culture system allows production to begin “without the need to adapt the virus strain to grow in eggs, as with traditional…technologies.”

The firm, which claims to have been asked to supply vaccine ingredients by more than 30 countries, said it will begin trials of its product next month and expects to obtain regulatory approval for the vaccine in the autumn.

In a follow up statement reported by London’s Financial Times yesterday, Novartis said that it “will not give free vaccines against H1N1 flu to poor countries, though it will consider discounts.”

GSK, Sanofi and CSL

The response of companies that use egg-based production methods was more uniform, with almost all saying that large-scale manufacture will begin by September at the earliest.

Initial media reports suggested that Australia’s CSL will finish making the first batch of its vaccine ahead of producers like GlaxoSmithKline (GSK) and Sanofi Aventis, although this was later denied by company spokesperson Rachel Davis.

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Qiagen Provides Solutions for Swine Flu Surveillance

Qiagen has announced that two of its tests can be used to screen for the swine flu virus. Data analysis of the viral gene sequences showed that the artus Influenza LC RT PCR Kit and the Resplex II 2.0 Kit, can be used to detect whether or not Influenza A virus sequences are present in a sample, including the H1N1 subtype. If the sample proves positive, treatment with medication such as Tamiflu or Relenza can be prescribed, according to the recommendations given by the corresponding drug manufacturers.

"We have compared the swine fever virus' sequence with our assays. The primers, which define the starting and end points of a genetic sequence that is amplified to make the target sequence visible, match 100 percent for the artus kit and almost 100 percent for the Resplex kit", said Dr Thomas Grewing, senior director, R&D. "We are now working closely with reference institutions to have both assays further re-validated and optimized based on clinical samples".

Both test kits are for research use only. They have not been cleared or approved by authorities including the United States Food and Drug Administration or any other regulatory agency in the United States, or under the European IVD Directive, for human diagnostic or other clinical use, and are not intended and should not be used for human diagnostic or any other clinical purposes.

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USDA Releasing Genomic Data from 150 Bird Flu Viruses

The United States Department of Agriculture has released the complete genetic sequences of 150 different avian influenza viruses and will make the information available through the National Institutes of Health’s GenBank.

The USDA said on Friday that the sequencing data is part of the federal government’s Initiative on Avian Influenza, and that this information will be combined with studies that compare the viruses’ ability to infect poultry such as chickens, turkeys, and domestic ducks.

This virus research that generated this data was conducted by the USDA’s Agricultural Research Service’s Southeast Poultry Research Laboratory (SEPRL), by the University of Georgia, the Ohio State University, the University of Delaware, and the University of Alaska-Fairbanks.

"The project's ultimate goal is to sequence 900 avian influenza viruses from the SEPRL repository," David Suarez, a researcher with SEPRL, said in a statement. "These include avian influenza viruses collected from both poultry and wild bird species in the United States and around the world.

"This sequence information, deciphered by our large team, will help researchers better understand virus biology and improve diagnostic tests for avian influenza viruses," Suarez added.

Sequencing services for the project were conducted by the Houston-based company SeqWright.

"Viruses are masters of cunning" - Imaging Of Influenza Virus Protein Opens Way To Design New Anti-viral Drugs

Already blogging about vital information that can be obtained form publications and scientific literature Smart tools to track, analyze and visualize research and the importance of Protein structure information in Protein structure databases with new web services for structural biology and biomedical research.

Now one of the tactics used by influenza virus to take over the machinery of infected cells has been laid bare by structural biologists at the European Molecular Biology Laboratory (EMBL) and the joint Unit of Virus Host-Cell Interaction of EMBL, the University Joseph Fourier and National Centre for Scientific Research (CNRS), in Grenoble, France.

The high-resolution image of the influenza virus' PB2 protein shows how the virus steals a 'cap' molecule from its host to take over the protein production machinery and multiply. PB2 binds the cap by sandwiching it between aromatic amino acids.

"Viruses are masters of cunning when it comes to hijacking the normal functioning of the host cell. The influenza virus steals a password from host messenger RNAs, molecules that carry the instructions for protein production, and uses it to gain access to the cell's protein-making machinery for its own purposes," says Cusack.

In the current issue of Nature Structural and Molecular Biology they publish a high-resolution image of a key protein domain whose function is to allow the virus to multiply by hijacking the host cell protein production machinery. The findings open the way for the design of new drugs to combat future influenza pandemics.