Locally anchoring enzymes to tissues via extracellular glycan recognition

Shaheen A. Farhadi, Evelyn Bracho-Sanchez, Margaret M. Fettis, Dillon T. Seroski, Sabrina L. Freeman, Antonietta Restuccia, Benjamin G. Keselowsky and Gregory A. Hudalla ()
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Shaheen A. Farhadi: University of Florida
Evelyn Bracho-Sanchez: University of Florida
Margaret M. Fettis: University of Florida
Dillon T. Seroski: University of Florida
Sabrina L. Freeman: University of Florida
Antonietta Restuccia: University of Florida
Benjamin G. Keselowsky: University of Florida
Gregory A. Hudalla: University of Florida

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Success of enzymes as drugs requires that they persist within target tissues over therapeutically effective time frames. Here we report a general strategy to anchor enzymes at injection sites via fusion to galectin-3 (G3), a carbohydrate-binding protein. Fusing G3 to luciferase extended bioluminescence in subcutaneous tissue to ~7 days, whereas unmodified luciferase was undetectable within hours. Engineering G3-luciferase fusions to self-assemble into a trimeric architecture extended bioluminescence in subcutaneous tissue to 14 days, and intramuscularly to 3 days. The longer local half-life of the trimeric assembly was likely due to its higher carbohydrate-binding affinity compared to the monomeric fusion. G3 fusions and trimeric assemblies lacked extracellular signaling activity of wild-type G3 and did not accumulate in blood after subcutaneous injection, suggesting low potential for deleterious off-site effects. G3-mediated anchoring to common tissue glycans is expected to be broadly applicable for improving local pharmacokinetics of various existing and emerging enzyme drugs.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07129-6

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DOI: 10.1038/s41467-018-07129-6

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