Development of a Therapeutic Collectin-11 Inhibitor to Minimize Ischemia Reperfusion Injuries

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Development of a Therapeutic Collectin-11 Inhibitor to Minimize Ischemia Reperfusion Injuries

Rachel Hevey 1 , Deborah Berta 1 , Mergim Maraj Martinez 1 , Tobias Wichers 1 , Tobias Brunner 1,2 , Martin Smiesko 2 , Said Rabbani 1 , Daniel Ricklin 1

1 Molecular Pharmacy, Dept. Pharmaceutical Sciences, University Of Basel, Basel, Switzerland, 2 Molecular Modeling, Dept. Pharmaceutical Sciences, University of Basel, Basel, Switzerland

The complement system is a complex pathway which plays an important role in innate immunity and as a first line of defense against invading organisms, damaged tissues, and maintenance of healthy cell populations. Despite its association with host defense, complement can turn against host cells when dysregulated or excessively triggered. Complement is considered a major contributor to various inflammatory diseases, and its lectin pathway has been implicated in transplantation- and ischemia-triggered clinical conditions. Specific inhibition of this initiation pathway may therefore pave the way for novel therapeutic approaches.

Among the potential targets are collectins, a family of C-type lectins which bind pathogen- or damage-associated molecular patterns (PAMPs/DAMPs), thereupon enhancing phagocytosis and/or inducing surface opsonization. Collectin-11 (CL-11, CL-K1) is broadly expressed in multiple tissue types and has been described as an activator of complement via the lectin pathway. It has been previously demonstrated that locally-produced CL-11 plays an important role in both acute kidney injury and late-stage/chronic renal inflammation, and that preventing CL-11 binding to the renal cell surface can reduce neutrophil filtration, C3d deposition, and tubular injury [1,2].

Given the inherently weak affinities of native carbohydrates for lectins, we have been focused on developing glycomimetic inhibitors of CL-11 with enhanced affinities and improved pharmacokinetic properties. Based on insights from in silico molecular dynamics simulations, we have constructed several glycomimetic libraries and evaluated them using biochemical and biophysical methods in efforts to eventually develop a therapeutic entity, as well as to further evaluate the biological role of CL-11.

Farrar, C.A.; et al. J. Clin. Invest. 2016, 126, 1911-1925.

Wu, W.; et al. J. Am. Soc. Nephrol. 2018, 29, 168-181.

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