The goal of this project is to generate pathway-specific therapeutic inhibitors for the study and treatment of complement-related diseases. Complement has been shown to play a role in various disorders ranging from inflammatory (e.g., periodontitis), immune, and degenerative, diseases to sepsis. Also, complement-related complications can be detrimental in biomaterial applications (e.g., hemodialysis) and transplant rejection. While the potential of inhibiting complement has long been recognized, therapeutic options are still limited, costly, do not include specific inhibitors of initiation and amplification steps, and are not readily available for research. Hence, extension and diversification of the inhibitory arsenal is desired both for therapy and as tools to dissect disease mechanisms. Starting from a panel of potent inhibitors discovered by our group or publicly disclosed, this project aims at generating a """"""""complement inhibitor toolbox"""""""" with broad use in the studies of this P01. The C3 inhibitor compstatin, which blocks initiation, amplification, and effector pathways, has shown clinical promise in many disease models, including transplantation, hemodialysis, and periodontitis, yet its pharmacokinetic (PK) profile and limited administration options render the use of this compound challenging in certain applications. We will therefore optimize the PK parameters of compstatin and evaluate its oral and subcutaneous administration in non-human primates. While inhibition of C3 has advantages, we will also develop inhibitors that specifically block the classical and alternative pathways. For the former, we will focus on a potent CIs-binding protein from leeches, which appears to bind both the catalytic and a potential exosite on CIs. By characterizing the activity of this protein and derived peptides, we will generate and optimize novel inhibitors for CIs. Based on factor H (FH) as a major host regulator of the alternative pathway, we rationally engineered a streamlined inhibitor with unique targeting properties toward diseased host cells and a potency that surpasses the parent protein FH. Terminal pathway inhibition will focus on anti- C5 antibodies and peptidomimetics available to this group, and the """"""""toolbox"""""""" will be completed by inhibitors Of the lectin pathway, the clinically used regulator C1-INH, and anaphylatoxin receptor antagonists. Finally, we explore novel strategies to direct complement inhibitors to foreign or diseased surfaces, where complement activation mainly occurs. For this purpose, we will modify compstatin and a newly discovered FHbinding peptide with anchors that allow attachment to cell membranes, self-cell surfaces, or biomaterials. All inhibitors and targeting options will be characterized for efficacy and specificity, and selected compounds will be subjected to production in Core B and evaluation in Projects 2 &3. Our integrated inhibitor development based on modular synthesis, potent lead structures and established techniques has high potential to pave the way to new clinical complement inhibitors and will be of great use for the study of complement diseases.
The purpose of this study is to develop compounds for the selective inhibition of the complement system. We will optimize promising candidate drugs and develop novel compounds that act at distinct stages of the complement cascade, thereby contributing to preclinical research and therapeutic applications. Optimized compounds will be evaluated in disease models to arrive at potent and specific inhibitors with clinical potential.
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