Biological Modeling Software Can Help Tame Inflammation in Arthritis
Biologists know about the seemingly endless functions of the NF-kB protein family. As a DNA-binding transcription inhibitor with a bevy of activators and several hundred distinct gene targets relevant to cell proliferation and inflammation, NF-kB has remained a hot research topic for a number of diverse sub-disciplines over the two decades since its first characterization.1 2 It’s no secret that NF-kB is hugely relevant to human health, although interventions which affect it must be perfectly calibrated to be successful. Recent advances in software-assisted nanoparticle design have paved the way for NF-kB targeted interventions in the context of osteoarthritic inflammation, as described in a presentation summarized in abstract in the Federation of American Societies for Experimental Biology Journal.3
The new research, conducted at the Washington University School of Medicine, boldly attempted to broadly inhibit NF-kB at the site of osteoarthritic joints via a self-assembling peptide nanoparticle. According to the researchers, the benefit of self-assembly is similar to that of a targeting mechanism. Because the nanoparticle only self-assembles at the site of the osteoarthritic inflammation, the dubious systemic effects of broad NF-kB inhibition are avoided. Thus, NF-kB’s inhibition suppresses joint inflammation in turn without causing immunosuppression.
Future researchers will likely dip their toes into the waters of systemic alteration of NF-kB using an even more carefully calibrated therapy. Using a nanopeptide complexed with genetic material seems like the most likely approach because it could theoretically contain the instructions for its own implementation according to the site of its gene silencing. After a certain point, nanopeptides with their own instruction sets to be interpreted by the recipient’s body might even be considered the much-fantasized “nanomachines” that futurists have long predicted.
Adding Some Flex to Treating Osteoarthritis
The new research has many potential downstream applications, ranging from treating acute impact injuries in joints to easing the stresses of aging on cartilage. To accomplish reducing inflammation, the nanoparticles designed by the researchers complex themselves with siRNA targeted at NF-kB’s gene, NFKB1. In the context of a recently damaged joint, the research found that suppressing NFKB1 resulted in fewer chondrocytes apoptosing over the few hours after injury. Less chondrocyte apoptosis leads to better maintenance of cartilage after an injury, which is critical for joint function and also comfort.4
Though the research was performed only in rodent osteoarthritis models, there’s reason to believe that the researchers’ broadly targeted but geographically restricted approach is viable for future treatments in humans. Despite NF-kB’s huge array of functions, nanoengineered peptides and designer siRNAs can provide stunning specificity of action, and aren’t especially expensive to produce.5 In terms of the laboratory formulation of a nanopeptide therapy targeted at osteoarthritic joints, even pioneers of nanotherapy have noted their easy generation.6 So, what’s the catch?
Designing An siRNA Complexing Self-Assembling Nanopeptide
The main challenge of developing a nanotherapy is design. For the geographical restriction of the therapy that the researchers designed to work, the following interactions have to be characterized:
- The biochemical complexing of the siRNA and the peptide during self assembly
- The nanopeptide’s general integrity after shearing during the mechanical pressure of injection into the wounded joint site
- The nanopeptide’s exposure of the siRNA component; is the peptide itself locked around the siRNA too tightly for it to form a complement with its target?
- The siRNA’s ability to ligate to its complement in the RISC complex7 to achieve gene silencing
- The integrity of the nanopeptide after successfully silencing NF-kB; does it remain bound to the RISC complex and prevent all activity, or does it detach and degrade?
- The durability and efficacy of remaining soluble nanopeptides in the environment of its own success; will the additional proliferation of synovial fluid at the injured joint wash out excess nanopeptide when it would still be therapeutic?
Most investigators will recognize that it’s possible to answer these questions experimentally, but that’s not a streamlined way that lends itself to useful therapeutic discovery. Understanding these interactions and answering these questions experimentally requires an abundance of time, models, and resources, which might offset the ease of use and relative cheapness of the nanopeptides and siRNAs. Using biological modeling software is the way to go when it comes to developing nanopeptide therapies.
Making A Model of Treating Inflammation
In the past, researchers resigned themselves to experimentation alone to answer their questions about molecular interactions and the complexing of their peptides with genetic materials. When developing a new peptide or seeking to sequence a new peptide, researchers were forced to use probabilistic methods and mass spectrometry alone to guide research.8 This lead to situations in which researchers weren’t even sure if the peptide that they’d designed on paper was reliably being synthesized into the product that they’d then try to complex with genetic material to create a prototype therapy. It’s no surprise that a lack of simulation ability led to longer development times, higher costs, and a boatload more frustration.
While experimentation is still necessary, using modeling software will reduce the amount of taking shots in the dark by a large amount. It allows researchers the ability to not only test new ideas in a low risk, low resource environment, it also allows them to leverage historical data to guide future work. Especially when it comes to developing complex systems like the new research’s nanopeptide system, having a powerful modeling suite as your ally during drug development makes the entire pipeline flow much smoother.
BIOVIA Biologics is the biological interaction simulation platform that your laboratory can use to develop nanopeptide therapeutics to conquer osteoarthritis. With Biologics, you’ll be able to design your constructs before generating them, preventing your team from wasting time testing constructs whose biochemistry is self contradictory.Contact us today to find out how you can use Biologics to fight osteoarthritis and other inflammation-based diseases.
- “NFKB1 nuclear factor kappa B subunit 1 (human).” June 2017, https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=4790. ↩
- “Cloning of the DNA-binding subunity of human nuclear factor kappa B: the level of its mRNA is strongly regulated by phorbol ester or tumor necrosis factor alpha.” February 1991, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC50935/. ↩
- “Anti-inflammatory Nanotherapy Targeting NF-kB In Experimental Osteoarthritis.” April 2016, http://www.fasebj.org/content/30/1_Supplement/1202.11.short. ↩
- “Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!)” January 2013, https://www.ncbi.nlm.nih.gov/pubmed/23194896. ↩
- “Recognition, Neutralization, and Clearance of Target Peptides in the Bloodstream of Living Mice by Molecularly Imprinted Polymer Nanoparticles: A Plastic Antibody.” April 2010, http://pubs.acs.org/doi/abs/10.1021/ja102148f. ↩
- “Peptides as targeting elements and tissue penetration devices for nanoparticles.” May 2012, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3947925/. ↩
- “Potent and pecific genetic interference by double-stranded RNA in Caenorhabditis elegans.” February 1998, https://www.ncbi.nlm.nih.gov/pubmed/9486653. ↩
- “PepNovo: De Novo Peptide Sequencing via Probabilistic Network Modeling.” January 2005, http://pubs.acs.org/doi/abs/10.1021/ac048788h. ↩