A team of researchers from The Scripps Research Institute (TSRI) and Janssen Research & Development (Janssen) has devised artificial peptide molecules that neutralize a broad range of influenza virus strains. Peptides are short chains of amino acids – like proteins but with smaller, simpler structures. These designed molecules have the potential to be developed into medicines that target influenza, which causes up to 500,000 deaths worldwide each year and costs Americans billions of dollars in sick days and lost productivity.
The developed peptides block the infectivity of most circulating strains of group 1 influenza A viruses, including H5N1, an avian flu strain that has caused hundreds of human infections and deaths in Asia, and the H1N1 swine flu strain that caused a global pandemic in 2009-10.
The scientists designed the peptides to mimic the virus-gripping regions of two recently discovered “super-antibodies” that are known to neutralize virtually all influenza A strains. Antibodies are large proteins that are expensive to produce and must be delivered by injection or infusion. Whereas, “the peptides developed in the study have the potential to be medicines delivered via pill-based drugs in the future.”
“Making small molecules that do essentially what these larger, broadly neutralizing antibodies do is a really exciting and promising strategy against influenza, as our new results show,” said co-senior investigator Ian Wilson, Hansen Professor of Structural Biology at TSRI.
The report on the new peptides appeared as an online First Release paper in Science on September 28, 2017.
The two anti-flu super-antibodies on which these peptides are based, called FI6v3 and CR9114, were discovered in 2011 and 2012. Since then, Wilson’s laboratory at TSRI in partnership with Janssen and other structural biology laboratories around the world have mapped at atomic scale how these and other broadly neutralizing antibodies bind to flu viruses.
A research team led by David Baker at the University of Washington recently used these antibody-structure data to design novel proteins, smaller than the antibodies, that bind to flu viruses in a similar way and neutralize a broad range of flu strains. The new effort by TSRI in collaboration with Janssen scientists aimed at the development of even smaller non-protein-like molecules that would hit the same target region on flu viruses.
Following several rounds of molecular design and synthesis, virus-binding testing, and atomic-level structural evaluation, the research team developed a set of four peptides with circular, “cyclic” structures that performed well as potential flu-blocking molecules.
The peptides showed high binding affinity for a broad set of group 1 influenza A viruses, as well as a potent ability to neutralize infections with these viruses in the laboratory experiments. The targeted group 1 influenza A viruses include H1, H2, H5 and H6 subtypes.
The peptides also incorporated amino-acid building blocks that are not found in natural proteins, and this, as well as their cyclic structures, made them relatively resistant to the enzymes that can otherwise quickly clear peptide drugs from the bloodstream. The most optimized of the four peptides, named P7, survived for hours when exposed to mouse or human blood plasma, or when injected into mice.
“These peptides have drug-like stability and will be good candidates for further testing of antiviral efficacy in animal models,” said Rameshwar U. Kadam, a senior postdoctoral research associate in the Wilson Laboratory who is co-first author of the study along with Jarek Juraszek, Principal Scientist at Janssen.
The peptides, like the antibodies they are designed to mimic, bind to a site known as the hydrophobic stem groove on the lower part of the flu virus’s main envelope protein hemagglutinin. The molecular structure at this site does not tend to vary much among flu strains because it plays a crucial role in a shape-shifting process that permits the virus to penetrate the host cell and initiate infection. Structural evaluations by Kadam found that the peptides prevent this shape-change and thus preventing host cell penetration.
“A therapy that targets the first stage of infection would complement the existing anti-influenza drugs that target later stages of infection,” Kadam said.
The peptides don’t bind to their viral target as comprehensively as the antibodies on which they are based. On group 2 influenza A viruses, for example, they lacked the bulkier antibodies’ ability to push aside or avoid a sugar molecule on the hemagglutinin that blocks a key part of the target site. However, Kadam said that further studies may yield peptides with activity against both group 1 and group 2 influenza A and even influenza B strains.
“It’s pretty revolutionary that we were able to use structural information on antibodies to make much smaller molecules that have almost the same binding affinity and breadth of neutralization against flu viruses,” said Kadam.
“There has been skepticism in the field that we could get such good results with such small molecules, but this study proves that we can,” Wilson said.
The Latest on: Artificial peptide molecules
- Nanopores make portable mass spectrometer for peptides a reality on February 19, 2019 at 12:24 pm
These pores are large protein structures, incorporated in a membrane. Molecules entering a pore or passing through ... We could engineer the nanopore with artificial amino acids, or use different ions ... […]
- Is Jello Good for You? Nutrition, Benefits, and Downsides on February 19, 2019 at 10:16 am
When the mixture cools, the collagen strands reform into a semi-solid state with water molecules trapped inside ... made with aspartame has only 13 calories, 1 gram of protein and no sugar. Still, art... […]
- At 8.3% CAGR, Protein Purification Market Size will reach 8060 million USD by 2023 on February 18, 2019 at 12:33 am
Sometimes the specific protein is caught in a matrix of other protein molecules, and sometimes it ... to absorb or reflect the UV rays that are contained in sun light or in artificial light. UV Filter... […]
- AI Is Rapidly Augmenting Healthcare and Longevity on February 15, 2019 at 7:30 am
Imagine leveraging cutting-edge artificial intelligence to accomplish with ... Zhavoronkov announced the groundbreaking result of generating novel molecules for a challenging protein target with an un... […]
- Newcastle University researchers 3D bioprint artificial cornea with self-assembling 4D biomaterials on February 13, 2019 at 3:42 am
Collagen gels that contain corneal cells (CCCGs) exhibit a contracting shrinkage, and Miotto and her team previously discovered that the presence of peptide amphiphile molecules inhibits the contracti... […]
- Artificial cornea breakthrough could lead to self-assembling organs on February 12, 2019 at 2:01 pm
Over the last decade, scientists have been testing artificial corneas made from synthetic collagen ... gels containing corneal cells contracted less when certain molecules (called peptide amphiphiles) ... […]
- New machine learning algorithm can help search new drugs on February 12, 2019 at 10:42 am
Machine learning is an application of artificial intelligence (AI ... From these, they identified four new molecules that activate the CHRM1 receptor, a protein that may be relevant for Alzheimer’s di... […]
- AI Gaining Ground in Drug Development on February 12, 2019 at 9:30 am
It’s not exactly breaking news that biopharma companies are increasingly turning toward machine learning and artificial intelligence (AI ... contest hosted by the Protein Structure Prediction Center, ... […]
- Drug Discovery Through Machine Learning Algorithm on February 11, 2019 at 11:12 pm
The researchers, led by the University of Cambridge, used their algorithm to identify four new molecules that activate a protein which is thought to be relevant for symptoms of Alzheimer's disease and ... […]
- Our artificial cornea breakthrough could lead to self-assembling organs on February 11, 2019 at 7:52 am
Over the last decade, scientists have been testing artificial corneas made from ... corneal cells contracted less when certain molecules (called peptide amphiphiles) were added. […]
via Google News and Bing News