Scientists discover a potential strategy to treat influenza A In a breakthrough with applicability across many flu strains, researchers find a potential small molecule that mimics antibodies to treat disease
March 11, 2019
LA JOLLA, CA A team of researchers from Scripps Research and Janssen Research & Development LLC has discovered an orally active small molecule that neutralizes influenza A group 1 viruses, the most common flu strains. Scientists uncovered the potential therapy in a large chemical library and optimized lead compounds to produce JNJ-4796. Now they have proven its effectiveness against influenza in mice.
What's exciting is that this molecule has the potential to target different strains and subtypes of influenza virus, says co-senior investigator Ian Wilson, PhD, Hansen Professor of Structural Biology at Scripps Research. Not only do influenza A type 1 viruses account for many of the seasonal flu strains, he says, but also pandemic strains, such as H1N1, and emerging strains, such as H5N1.
In a typical year, influenza sickens 5 to 20 percent of the U.S. population, leading to more than 200,000 hospitalizations and 36,000 deaths, according to the Centers for Disease Control and Prevention. Strains of influenza A virus are categorized into group 1 and group 2, and then into further subtypes. Antibodies against the virus often only recognize a handful of similar strains. However, a decade ago, Wilson was part of a team of researchers who described a super- antibody called CR6261 isolated from a healthy human that recognized a part of the virus called the hemagglutinin (HA) stem, which is present across influenza strains.
Since that time, researchers have been striving to use these super-antibodies, known as broadly neutralizing antibodies (bnAbs), to develop approaches which could lead to universal flu vaccines and treatments. However, antibodies themselves are large molecules that can only be given through injections, never as an oral drug, which makes them impractical for treating patients at home. A more practical drug, Wilson theorized, would consist of a small molecule that recognizes the HA stem in the same way as the antibody.
In 2017, researchers at Janssen and Scripps designed an artificial peptide that bound to the same region of the HA stem as CR6261 using information on how other stem bnAbs, FI6v3 and CR9114, bind to and neutralize influenza virus. In the new work, published online in the journal Science, they've taken a different approach to mimicking the antibody's actions.
The researchers turned to a library of more than 500,000 drug-like molecules and, in a high-throughput experiment, tested whether any of the compounds could displace a small protein HB80.4 mimic of bnAb CR6261 from the influenza type 1 HA stem, suggesting that such molecules attached to the same spot on the virus. Multiple molecules turned up as positive on the screen, and optimization to produce better binding and pharmacokinetic properties resulted in JNJ-4796 being the most promising inhibitor. Structural work in the Wilson lab revealed the close mimicry of how JNJ4796 bound to the HA stem compared to bnAb CR6261.
The team went on to show that when mice were given JNJ-4796 for seven days, beginning one day before being infected with 25 times the normally-lethal dose of H1N1 influenza, 100 percent of the mice survived. Moreover, when JNJ-4796 was incubated with human bronchial epithelial cells airway cells affected by a flu infection the compound dramatically lowered levels of the virus present in the tissue 96 hours after infection.
While the current version of JNJ-4796 targets the HA stem of influenza A group 1 viruses, the study revealed structural information on how the molecule binds to the HA stem and what changes could possibly make it act more broadly against other influenza strains. While this manuscript suggests that this may be a potential strategy for the treatment of influenza A, this study was pre-clinical, and further studies would be warranted to pursue this approach.
In addition to pointing towards a potential strategy for the design of new drugs to treat influenza, the new work opens the door to designing other antiviral drugs using a similar antibody-inspired approach.
The molecule is proof-of-principle that antibody-guided drug discovery can work, says co-first author Rameshwar U. Kadam, PhD, a senior research associate at Scripps Research. We can now apply this approach to a whole host of other viruses.
Kadam adds that HIV and Ebola for which neutralizing antibodies are known would be especially useful to study in the same way. While antibodies can cost thousands of dollars per dose, small molecules are cheaper, more shelf-stable, and can be developed into oral compounds that are more convenient for patients. Further research would be required.
In addition to Wilson, van Dongen, and Kadam, authors of the study, A small-molecule fusion inhibitor of influenza virus is orally active in mice, include Divita Garg and Wenli Yu of Scripps Research; and Jarek Juraszek, Edward Lawson, Boerries Brandenburg, Frederike Schmitz, Wim B. G. Schepens, Bart Stoops, Harry A. van Diepen, Mandy Jongeneelen, Chan Tang, Jan Vermond, Alida van Eijgen-Obregoso Real, Sven Blokland, Wouter Goutier, Ellen Lanckacker, Jaco M. Klap, Dani lle C. G. Peeters, Jin Wu, Christophe Buyck, Tim H. M. Jonckers, Dirk Roymans, Peter Roevens, Ronald Vogels, Wouter Koudstaal, Robert H. E. Friesen, Pierre Raboisson, Dashyant Dhanak, and Jaap Goudsmit of Janssen.
This work was supported by funding from the National Institutes of Health (R56 AI117675 and R56 AI127371) and the Swiss National Science Foundation. Use of the Stanford Synchrotron Radiation Lightsource to collect x-ray datasets was supported by the U.S. Department of Energy (contract DE-AC02-76SF00515). The SSRL Stru
Most recent headlines
04/08/2024
Dalet, a leading technology and service provider for media-rich organizations, is excited to announce Santiago Solanas as its new Chief Executive Officer (CEO)....
03/06/2024
Dalet, a leading technology and service provider for media-rich organizations, a...
28/04/2024
Mediahaus delivers the first SRT live-streaming sports production over 5G with U...
27/04/2024
On April 26, L3Harris Chair and CEO Christopher E. Kubasik joined CNBC's Mor...
27/04/2024
PORTLAND, Oregon Audinate Group Limited, the developer of the Dante AV-over-IP solution, announced significant new additions to Dante Connect, its cloud-based D...
27/04/2024
TORONTO Bell Media has launched 10 English and French-language FAST channels featuring entertainment, factual, news, and sports programming. The new free stream...
27/04/2024
An extensive new analysis of the news segments in the broadcast evening news programs of ABC, CBS, NBC and PBS has found that broadcasters devoted most of their...
27/04/2024
GERMANTOWN, Md. EchoStar's Hughes Network Systems has opened a new manufacturing facility and private 5G incubation center in Germantown, Maryland....
27/04/2024
Harry Pappas, one of three brothers who founded Pappas Telecasting Companies in 1971, died April 24. He was 78 years old....
27/04/2024
ATLANTA and LONDON Mexican telecommunications and broadcast company Televisa has selected Synamedia for an overhaul of its broadcast distribution....
27/04/2024
Participate in the Survey - The Impact of AI on Media and the Creative Industry
Pascal Wagner April 26, 2024
0 Comments
By participating in this surve...
27/04/2024
SDVI Rally Access Workstation Earns Two Top Awards at 2024 NAB Show
Brie Clayton April 26, 2024
0 Comments
SDVI, the leading platform provider for clo...
27/04/2024
Berklee's Music and Health Institute Launches Community Health Musician Cert...
27/04/2024
Charter Communications reported higher first-quarter profits despite continued cord-cutting and competition for broadband customers....
27/04/2024
Two environmentally-focused groups are partnering to engage the unscripted TV world in finding better ways to address climate change. Reality of Change is an ec...
27/04/2024
Sarah Garcia has been promoted to weekend anchor at KTLM McAllen, Texas, known as Telemundo 40. Starting April 27, she will anchor Noticias Telemundo 40 weekend...
27/04/2024
CBS Sports said it launched a new 24-hour free, ad supported streaming television (FAST) channel devoted to the UEFA Champions League....
27/04/2024
Comcast chairman and CEO Brian Roberts received $35.4 million in compensation in 2023, up 11% from the previous year, according to a proxy statement filed by th...
27/04/2024
Art Happens Here With John Lithgow, which sees the actor study dance, ceramics, silk-screen printing and vocal jazz with students in Los Angeles, debuts on PBS ...
27/04/2024
Remember Leave It to Beaver? Bewitched? Dragnet? When cable ratings were rising?...
27/04/2024
Next up for the weekend binge at Catchy Comedy is Gomer Pyle, U.S.M.C. Every weekend, Catchy Comedy features The Catchy Binge, a marathon of a classic sitcom....
26/04/2024
Sundance Film Festival CDMX 2024 kicks-off today with screenings in 5 theaters in Mexico City and the opening-night film, FRIDA, directed by Carla Guti rrez...
26/04/2024
[Editor's Note: This interview is part of a larger feature about the women d...
26/04/2024
Once again this year, SGL Carbon opened its doors to interested children and young people. On the occasion of the German Girls and Boys Day, which took place on...
26/04/2024
Orders1 of $5.5 billion; book-to-bill of 1.06x
Revenue of $5.2 billion, up 17%,...
26/04/2024
Five Considerations For Communications Modernization In The 21st Century
In the digital-enabled battlespace, the Joint Force needs to shoot, move and communica...
26/04/2024
CBS Sports has launched Champions League as a new, 24-hour streaming channel that will serve as the year-round destination for nonstop highlights of the UEFA ...
26/04/2024
Despite tough competition in the streaming space, Roku reported solid results in Q1 2024, beating revenue expectations, with total net revenue up 19% YoY to $88...
26/04/2024
LONDON AND TORONTO Pinewood Toronto Studios has appointed Sarah Farrell as general manager of the Studios in downtown Toronto....
26/04/2024
Quantum to Offer Advanced Filesharing Technology and Performance in StorNext and...
26/04/2024
FilmLight Colour Awards welcomes 2024 entries and introduces new Emerging Talen...
26/04/2024
Picture Shop Announces Chris Evans as Head of Unscripted
Brie Clayton April 26, 2024
0 Comments
Picture Shop announced Chris Evans will lead Unscripte...
26/04/2024
Participate in a Survey - The Impact of AI on Media and the Creative Industry
Pascal Wagner April 26, 2024
0 Comments
By participating in this survey,...
26/04/2024
Toy maker Mattel said it is working with Samsung to launch its first free ad-supported streaming television (FAST) channels later this year....
26/04/2024
Trusted Media Brands (TMB) said it named Marty Moe as president....
26/04/2024
Ron Howard is the director on Jim Henson Idea Man, a documentary that premieres on Disney Plus May 31. Henson of course created Kermit the Frog, Miss Piggy, Big...
26/04/2024
The ice continues to melt under the regional sports network business as the Seattle Kraken of the National Hockey League have made a long-term deal to broadcast...
26/04/2024
Heading into the upfronts, Warner Bros. Discovery said it launched Olli, a first-party data platform advertiser can use for converged, targeted advertising camp...
26/04/2024
CBS has renewed the drama The Equalizer, which will see season five on in 2024-2025. Queen Latifah stars....
26/04/2024
The CW has entered into an exclusive multiyear broadcast partnership for the Miss USA Pageant and the Miss Teen USA Pageant. The 73rd Miss USA Pageant will air ...
26/04/2024
Fuse Media isn't mincing words in a campaign urging its young viewers to register and participate in the 2024 elections....
26/04/2024
Dead Boy Detectives, a series from Neil Gaiman about a detective agency staffed by ghosts, debuts on Netflix April 25. George Rexstrew and Jayden Revri are in t...
26/04/2024
The Story Collective has gradually repurposed the former Mortlake Brewery to include production offices, workshops and sound stages
By Matthew Corrigan
Publi...
26/04/2024
Perkett joins the company following a 25 year career in product management, product marketing, engineering and user experience (UX) across multiple industries
...
26/04/2024
Teradek, the industry leader in wireless video transmitters and receivers, announced today the launch of new Bolt 6 LT 750 and Bolt 6 Monitor Module 750 RX with...
26/04/2024
NEW YORK Amagi has appointed Richard Perkett chief product officer (CPO)....
26/04/2024
WASHINGTON, D.C. The National Association of Broadcasters (NAB) has announced the results of the 2024 NAB Radio and Television Board of Directors elections. The...
26/04/2024
EL SEGUNDO, Calif. & NEW YORK Mattel has announced a deal to launch its first three 24/7 free ad supported streaming (FAST) channels on Samsung TV Plus, Samsung...
26/04/2024
PORTLAND, Maine Viewers here can now receive the NextGen TV signals of five local stations with the launch of ATSC 3.0 service from host station WPFO, which is ...
Scientists discover a potential strategy to treat influenza A In a breakthrough with applicability across many flu strains, researchers find a potential small molecule that mimics antibodies to treat disease
