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Inspired by Nature: New Therapeutic Modalities to Control Adverse Complement & Coagulation Reactions in Immune and Thrombo-Inflammatory Conditions

Research Project
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01.11.2021
 - 31.10.2023

The therapeutic strategy is based on the biological features of a parasitic protein, which we have termed 'leech inhibitor of host defence responses' (LIHDR). Its activity against initiating SP of complement and coagulation (incl. C1s, MASP2, FXIIa) renders LIHDR attractive for early, upstream inhibition of adverse defence responses. Despite its structural complexity, we managed to produce highly active LIHDR analogues in prokaryotic expression systems, which greatly facilitates structure-activity-relationship (SAR) studies and protein engineering. In in vitro studies, recombinant LIHDR analogues showed favourable efficacy profiles. Using experimental and computational methods, we are elucidating molecular determinants of target activity/selectivity/specificity and already generated LIHDR analogues with shifted SP selectivity, indicating a potential to produce inhibitors with broad or narrow SP-inhibitory activity. Our extensive SAR is also expected to identify common hot-spot areas on host SP that may be targeted by antibodies or other entities. Testing multi- and monospecific analogues of the same inhibitor in relevant disease models may provide an ideal platform for evaluating therapeutic strategies in defence-triggered disorders.

Funding

Inspired by Nature: New Therapeutic Modalities to Control Adverse Complement & Coagulation Reactions in Immune and Thrombo-Inflammatory Conditions

Industriegelder, Sonstige Forschungskooperationen (GrantsTool), 11.2021-10.2023 (24)
PI : Ricklin, Daniel.
CI : Lill, Markus A..

Members (3)

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Daniel Ricklin

Principal Investigator
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Markus A. Lill

Co-Investigator
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Peter Rüthemann

Project Member