Projects & Collaborations 4 foundShow per page10 10 20 50 Specificity, selectivity and pharmacokinetics of compstatin: a comprehensive multidisciplinary analysis Research Project | 6 Project MembersThe complement system plays a major role in innate immunity as it confers immune surveillance and first-line defense against non- or altered-self entities such as microbes or apoptotic cells. Yet, misguided complement activation may trigger or contribute to severe clinical conditions or complications, including autoimmune, hemolytic, inflammatory and age-related disorders and transplant rejection (PMID) [1]. Owing to its cascade organization, involving ~50 plasma proteins, receptors and enzymes, complement provides multiple points for novel pharmacological intervention [2]. However, few complement-targeted drugs have reached the clinic, and the available options primarily target peripheral steps in cascade initiation or effector generation. For many acute-phase or multifactorial complement disorders, blocking the activation of the central complement component C3 is considered important [3]. Derivatives of compstatin, a peptidic inhibitor of C3 activation [4], are the most advanced compounds in this class, with two candidate drugs being evaluated in clinical trials. However, its narrow species-specificity for primate C3 currently restricts a broader exploration of potential benefits of C3 inhibition in various established animal models of complement disorders. Furthermore, despite considerable progress in structure optimization, some pharmacokinetic and physicochemical properties of the compstatin class remain to be improved to fully unleash its unique therapeutic potential. The main objective of this project is to understand target binding and complement inhibition by compstatin in the human system at the atomic level and identify key determinants of its narrow species specificity. We will utilize this knowledge for designing compstatin analogs that recognize non-primate C3 and, for example, inhibit mouse, rat or pig complement. Simultaneously, we will assess compstatin's target selectivity for C3 over the orthologous C4 and C5 proteins and explore options for achieving C4-, C5- or pan-specific inhibitors for research or clinical applications. Finally, we will analyze and optimize the pharmacokinetic properties of compstatin with special emphasis on solubility and bioavailability. The proposed rationalization and optimization efforts will be driven by well-established in silico simulation techniques such as molecular dynamics simulations, free energy methods, homology modeling, and post-MD analyses, supported by novel approaches based on deep learning (Prof. Markus Lill, Computational Pharmacy). Thanks to project collaborations with strong experimental groups, in silico findings will be experimentally verified by employing peptide synthesis and characterization, chemical modification and labeling, and target binding and functional assays in vitro (Prof. Daniel Ricklin, Molecular Pharmacy) as well as pre-clinical assessments of cellular permeability in vitro and in vivo (Prof. Henriette Meyer zu Schwabedissen, Biopharmacy; all at University of Basel). Our studies are expected to extend preclinical evaluation options of compstatin-based drugs in animal models and enhance their pharmacokinetic profile, thereby facilitating clinical development of this important inhibitor class. Selectivity studies with C4/C5 may provide insight into complement activation and potentially reveal novel inhibitors. Finally, atomic level insight into the structure-activity/property relationships of cyclic peptides may be used for the design of this compound type in general. [1] Ricklin, D.; Reis, E. S.; Lambris, J. D. Complement in Disease: A Defence System Turning Offensive. Nat. Rev. Nephrol. 2016, 12 (7), 383-401. https://doi.org/10.1038/nrneph.2016.70. [2] Mastellos, D.C., Ricklin, D. & Lambris, J.D. Clinical promise of next-generation complement therapeutics. Nat Rev Drug Discov 18, 707-729 (2019). https://doi.org/10.1038/s41573-019-0031-6 [3] Mastellos, D. C.; Reis, E. S.; Ricklin, D.; Smith, R. J.; Lambris, J. D. Complement C3-Targeted Therapy: Replacing Long-Held Assertions with Evidence-Based Discovery. Trends Immunol. 2017, 38 (6), 383-394. https://doi.org/10.1016/j.it.2017.03.003. [4] Mastellos, D. C.; Yancopoulou, D.; Kokkinos, P.; Huber-Lang, M.; Hajishengallis, G.; Biglarnia, A. R.; Lupu, F.; Nilsson, B.; Risitano, A. M.; Ricklin, D.; Lambris, J. D. Compstatin: A C3-Targeted Complement Inhibitor Reaching Its Prime for Bedside Intervention. Eur. J. Clin. Invest. 2015, 45 (4), 423-440. https://doi.org/10.1111/eci.12419. Novel treatment approach to enable blood group-incompatible transplantations Research Project | 2 Project MembersTransplant shortages have necessitated blood group-incompatible organ/stem cell transplantation. To ease organ deficit and improve patients' lives, we have designed glycopolymers to selectively remove circulating antibodies, reducing dependence on immunosuppresants and associated infection risk. Therapeutic Modulation of Adverse Host Defense System Activation on Biomaterial and Cell Surfaces Research Project | 3 Project MembersUnder normal circumstances, the host defense functions of the human complement system help protecting our bodies from microbial threats and accumulating debris. However, the unique ability of complement to swiftly recognize foreign surfaces may suddenly turn into a burden when we are exposed to biomaterials, drug delivery vehicles, and cell or solid organ transplants. Prevention of complement activation directly on such non-self surfaces via protective coating is therefore considered a promising strategy for avoiding inflammatory complications. This proposal aims to design small complement-modulatory entities as a platform technology to be employed either as a surface coating or as a "molecular bridge" that guides physiological complement regulators to tissue, cell or material surfaces facing adverse activation of host defense pathways. The central element of our efforts is the cyclic peptide 5C6, which binds to the major complement regulator in circulation (i.e., Factor H; FH) and recruits it to 5C6-coated surfaces. The first stage of our research plan is focused on elucidating a structure-activity relationship profile of 5C6 to improve binding affinity, stability, and functionalization efficacy. For optimal activity, 5C6 needs to be coated on or tethered to a cell or material surface. The second stage of the proposal therefore aims at identifying promising coupling/targeting entities by focusing on three model systems: 1) liposomal formulations used as drug delivery vehicle; 2) endothelial cells relevant to transplantation; and 3) erythrocytes as a frequent target of erroneous complement attack. Coupling/targeting moieties will be evaluated for their selectivity and suitability to be linked to 5C6. In the third stage, suitable candidate compounds will be evaluated for their ability to prevent complement activation in the respective applications using established models. These targeted, FH-binding peptides are expected to provide attractive options for therapeutic modulation of complement activity on cells and surfaces with broad applicability of this versatile platform technology in transplantation medicine, inflammatory conditions and beyond. PhD4GlycoDrug Research Project | 3 Project MembersThe PhD4GlycoDrug consortium has a main goal to offer a European Joint Doctorate educational training network in Glyco-Drug Discovery and Development . The network combines 6 academic partners with long tradition in PhD training and accredited doctoral studies in Organic Chemistry, Medicinal Chemistry, Structural Biology and Pharmacology/Pharmacy. Non-academic partners, 4 SMEs and a research institute also constitute the consortium to offer intersectoral exposure and quality training in transferable skills to entrepreneurial ESRs. So far, only a handful of registered drugs originate from glycoscience area. To pursue an innovative research project in such a timely scientific field of great interest for pharmaceutical industry, a specific set of competences is needed. Our network will focus on delivering expert researchers highly attractive for employment by the European Pharma-industry. 1 1
Specificity, selectivity and pharmacokinetics of compstatin: a comprehensive multidisciplinary analysis Research Project | 6 Project MembersThe complement system plays a major role in innate immunity as it confers immune surveillance and first-line defense against non- or altered-self entities such as microbes or apoptotic cells. Yet, misguided complement activation may trigger or contribute to severe clinical conditions or complications, including autoimmune, hemolytic, inflammatory and age-related disorders and transplant rejection (PMID) [1]. Owing to its cascade organization, involving ~50 plasma proteins, receptors and enzymes, complement provides multiple points for novel pharmacological intervention [2]. However, few complement-targeted drugs have reached the clinic, and the available options primarily target peripheral steps in cascade initiation or effector generation. For many acute-phase or multifactorial complement disorders, blocking the activation of the central complement component C3 is considered important [3]. Derivatives of compstatin, a peptidic inhibitor of C3 activation [4], are the most advanced compounds in this class, with two candidate drugs being evaluated in clinical trials. However, its narrow species-specificity for primate C3 currently restricts a broader exploration of potential benefits of C3 inhibition in various established animal models of complement disorders. Furthermore, despite considerable progress in structure optimization, some pharmacokinetic and physicochemical properties of the compstatin class remain to be improved to fully unleash its unique therapeutic potential. The main objective of this project is to understand target binding and complement inhibition by compstatin in the human system at the atomic level and identify key determinants of its narrow species specificity. We will utilize this knowledge for designing compstatin analogs that recognize non-primate C3 and, for example, inhibit mouse, rat or pig complement. Simultaneously, we will assess compstatin's target selectivity for C3 over the orthologous C4 and C5 proteins and explore options for achieving C4-, C5- or pan-specific inhibitors for research or clinical applications. Finally, we will analyze and optimize the pharmacokinetic properties of compstatin with special emphasis on solubility and bioavailability. The proposed rationalization and optimization efforts will be driven by well-established in silico simulation techniques such as molecular dynamics simulations, free energy methods, homology modeling, and post-MD analyses, supported by novel approaches based on deep learning (Prof. Markus Lill, Computational Pharmacy). Thanks to project collaborations with strong experimental groups, in silico findings will be experimentally verified by employing peptide synthesis and characterization, chemical modification and labeling, and target binding and functional assays in vitro (Prof. Daniel Ricklin, Molecular Pharmacy) as well as pre-clinical assessments of cellular permeability in vitro and in vivo (Prof. Henriette Meyer zu Schwabedissen, Biopharmacy; all at University of Basel). Our studies are expected to extend preclinical evaluation options of compstatin-based drugs in animal models and enhance their pharmacokinetic profile, thereby facilitating clinical development of this important inhibitor class. Selectivity studies with C4/C5 may provide insight into complement activation and potentially reveal novel inhibitors. Finally, atomic level insight into the structure-activity/property relationships of cyclic peptides may be used for the design of this compound type in general. [1] Ricklin, D.; Reis, E. S.; Lambris, J. D. Complement in Disease: A Defence System Turning Offensive. Nat. Rev. Nephrol. 2016, 12 (7), 383-401. https://doi.org/10.1038/nrneph.2016.70. [2] Mastellos, D.C., Ricklin, D. & Lambris, J.D. Clinical promise of next-generation complement therapeutics. Nat Rev Drug Discov 18, 707-729 (2019). https://doi.org/10.1038/s41573-019-0031-6 [3] Mastellos, D. C.; Reis, E. S.; Ricklin, D.; Smith, R. J.; Lambris, J. D. Complement C3-Targeted Therapy: Replacing Long-Held Assertions with Evidence-Based Discovery. Trends Immunol. 2017, 38 (6), 383-394. https://doi.org/10.1016/j.it.2017.03.003. [4] Mastellos, D. C.; Yancopoulou, D.; Kokkinos, P.; Huber-Lang, M.; Hajishengallis, G.; Biglarnia, A. R.; Lupu, F.; Nilsson, B.; Risitano, A. M.; Ricklin, D.; Lambris, J. D. Compstatin: A C3-Targeted Complement Inhibitor Reaching Its Prime for Bedside Intervention. Eur. J. Clin. Invest. 2015, 45 (4), 423-440. https://doi.org/10.1111/eci.12419.
Novel treatment approach to enable blood group-incompatible transplantations Research Project | 2 Project MembersTransplant shortages have necessitated blood group-incompatible organ/stem cell transplantation. To ease organ deficit and improve patients' lives, we have designed glycopolymers to selectively remove circulating antibodies, reducing dependence on immunosuppresants and associated infection risk.
Therapeutic Modulation of Adverse Host Defense System Activation on Biomaterial and Cell Surfaces Research Project | 3 Project MembersUnder normal circumstances, the host defense functions of the human complement system help protecting our bodies from microbial threats and accumulating debris. However, the unique ability of complement to swiftly recognize foreign surfaces may suddenly turn into a burden when we are exposed to biomaterials, drug delivery vehicles, and cell or solid organ transplants. Prevention of complement activation directly on such non-self surfaces via protective coating is therefore considered a promising strategy for avoiding inflammatory complications. This proposal aims to design small complement-modulatory entities as a platform technology to be employed either as a surface coating or as a "molecular bridge" that guides physiological complement regulators to tissue, cell or material surfaces facing adverse activation of host defense pathways. The central element of our efforts is the cyclic peptide 5C6, which binds to the major complement regulator in circulation (i.e., Factor H; FH) and recruits it to 5C6-coated surfaces. The first stage of our research plan is focused on elucidating a structure-activity relationship profile of 5C6 to improve binding affinity, stability, and functionalization efficacy. For optimal activity, 5C6 needs to be coated on or tethered to a cell or material surface. The second stage of the proposal therefore aims at identifying promising coupling/targeting entities by focusing on three model systems: 1) liposomal formulations used as drug delivery vehicle; 2) endothelial cells relevant to transplantation; and 3) erythrocytes as a frequent target of erroneous complement attack. Coupling/targeting moieties will be evaluated for their selectivity and suitability to be linked to 5C6. In the third stage, suitable candidate compounds will be evaluated for their ability to prevent complement activation in the respective applications using established models. These targeted, FH-binding peptides are expected to provide attractive options for therapeutic modulation of complement activity on cells and surfaces with broad applicability of this versatile platform technology in transplantation medicine, inflammatory conditions and beyond.
PhD4GlycoDrug Research Project | 3 Project MembersThe PhD4GlycoDrug consortium has a main goal to offer a European Joint Doctorate educational training network in Glyco-Drug Discovery and Development . The network combines 6 academic partners with long tradition in PhD training and accredited doctoral studies in Organic Chemistry, Medicinal Chemistry, Structural Biology and Pharmacology/Pharmacy. Non-academic partners, 4 SMEs and a research institute also constitute the consortium to offer intersectoral exposure and quality training in transferable skills to entrepreneurial ESRs. So far, only a handful of registered drugs originate from glycoscience area. To pursue an innovative research project in such a timely scientific field of great interest for pharmaceutical industry, a specific set of competences is needed. Our network will focus on delivering expert researchers highly attractive for employment by the European Pharma-industry.
