Advances in Nucleic-Based Therapeutics

WASHINGTON, March 16, 2021 /PRNewswire/ -- An article published in Experimental Biology and Medicine (Volume 246, Issue 6, March, 2021) reports a new nucleic acid-based approach for therapeutics targeting inflammation. The study, led by Dr. Anthony Bell Jr, in the Department of Chemistry and Biochemistry at the University of San Diego in San Diego, CA (USA), reports four novel cruciform DNA ligands that exhibit increased nuclease-resistance, thermostability, and target-binding affinity. 

HMGB1 (High Mobility Group B1) is an important molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. HMGB1 plays two different but critical roles inside and outside of cells. Inside cells, HMGB1 bends DNA into arrangements or scaffolds that facilitate gene expression. Outside cells, HMGB1 functions as a proinflammatory cytokine that can be either a "friend" or "foe" and initiate cytokine reactions that ward off harmful stimuli or worsen autoimmune dysfunction. Previous work has shown that nucleic acids directed against HMGB1 can be used to block HMGB1 function. Nonetheless, the clinical use of nucleic therapeutics is hampered by their thermal instability, short half-life due to degradation by endogenous nucleases, and low binding affinity for their target.

In the current study, Dr. Bell and colleagues used a targeting strategy that merges both the intracellular and extracellular roles of HMGB1 to design four novel cruciform DNA ligands to target HMGB1. Natural and non-standard nucleic acid bonds (e.g. phosphorothioate bonds) were included to prevent the DNA ligands from being rapidly cleared from the body. Hairpin loop regions were included to prevent decomposition at high temperatures. Both design modifications significantly enhanced nuclease and thermal stability. Finally, the cruciform DNA ligands bound HMGB1 with extremely high affinity. The successful design of DNA ligands with enhanced biophysical stability and HMGB1 binding affinity represent significant advances in the field. Dr. Bell said "HMGB1 is a notoriously difficult protein to target due to its sheer abundance, biochemical composition and multifunctional properties. We chart a different course in using modified DNA ligands to sequester HMGB1. We are proud of the advances made thus far and strongly believe that this approach may one day be used in a stand-alone or combined regime to treat HMGB1 related diseases."   

Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology & Medicine, said "Dr. Anthony Bell Jr and colleagues have performed interesting studies on the classic branched DNA four-way junction construct, Ji, to identify a design strategy that enhances thermostability and nuclease resistance. They found that introducing H2-type mini-hairpin junctions provides the desired characteristics while increasing affinity to HMGB1. The current work, followed by future in vivo studies with these constructs, will provide an important advance towards nucleic acid therapeutics for the treatment of HMGB1 related disorders."

Experimental Biology and Medicine is a global journal dedicated to the publication of multidisciplinary and interdisciplinary research in the biomedical sciences. The journal was first established in 1903. Experimental Biology and Medicine is the journal of the Society of Experimental Biology and Medicine. To learn about the benefits of society membership visit www.sebm.org. If you are interested in publishing in the journal, please visit http://ebm.sagepub.com/.

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SOURCE Experimental Biology and Medicine