Molecular Pharmacy (Ricklin)Head of Research Unit Prof. Dr.Daniel RicklinOverviewMembersPublicationsProjects & CollaborationsProjects & Collaborations OverviewMembersPublicationsProjects & Collaborations Projects & Collaborations 16 foundShow per page10 10 20 50 Design, synthesis, and evaluation of collectin-11 inhibitors for biomedical research and therapeutic development Research Project | 2 Project MembersImported from Grants Tool 4707200 Mucin O-glycans as regulators of pathogen virulence: glycan synthesis, mechanistic investigation, and therapeutic potential Research Project | 3 Project MembersImported from Grants Tool 4702942 Utilizing Factor H-Binding Peptides for the Protection of Xenotransplants from Complement-Mediated Damage Research Project | 1 Project MembersImported from Grants Tool 4705591 Helostasin - A Novel Complement Pathway Modulator Research Project | 4 Project MembersImported from Grants Tool 4702675 Leech-Derived Bivalent Peptide Inhibitors of Complement Initiating Proteases Research Project | 2 Project MembersImported from Grants Tool 4700693 ComplemenTED: An Integrated Platform for Complement Therapeutics Evaluation and Development Research Project | 1 Project MembersNo Description available Development of glycan-based antimicrobial therapies Research Project | 3 Project MembersAntimicrobial resistance is reaching a global crisis and the WHO considers it a major health threat. Alternative therapies for infection are urgently needed, therefore we have developed a novel drug class targeting a range of pathogens while retaining natural flora to restore microbiome homeostasis. Treatment of viral infections with glycopolymers Research Project | 1 Project MembersThe proposed project aims to develop a dual therapeutic approach to combat viral infections (with a focus on SARS-CoV-2) by preventing viral entry and dissemination. Firstly, by inhibiting trans-infection (mediated by DC SIGN) and secondly, by inhibiting initial viral attachment via heparan sulphate (HS) and related negatively charged epitopes on host cells. This can be achieved by presenting DC-SIGN ligands and HS subunits (or glycomimetics/analogues thereof) multivalently on a biodegradable scaffold to inhibit viral attachment and dissemination with high specificity and efficiency. Inspired by Nature: New Therapeutic Modalities to Control Adverse Complement & Coagulation Reactions in Immune and Thrombo-Inflammatory Conditions Research Project | 3 Project MembersThe 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. 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. 12 12 OverviewMembersPublicationsProjects & Collaborations
Projects & Collaborations 16 foundShow per page10 10 20 50 Design, synthesis, and evaluation of collectin-11 inhibitors for biomedical research and therapeutic development Research Project | 2 Project MembersImported from Grants Tool 4707200 Mucin O-glycans as regulators of pathogen virulence: glycan synthesis, mechanistic investigation, and therapeutic potential Research Project | 3 Project MembersImported from Grants Tool 4702942 Utilizing Factor H-Binding Peptides for the Protection of Xenotransplants from Complement-Mediated Damage Research Project | 1 Project MembersImported from Grants Tool 4705591 Helostasin - A Novel Complement Pathway Modulator Research Project | 4 Project MembersImported from Grants Tool 4702675 Leech-Derived Bivalent Peptide Inhibitors of Complement Initiating Proteases Research Project | 2 Project MembersImported from Grants Tool 4700693 ComplemenTED: An Integrated Platform for Complement Therapeutics Evaluation and Development Research Project | 1 Project MembersNo Description available Development of glycan-based antimicrobial therapies Research Project | 3 Project MembersAntimicrobial resistance is reaching a global crisis and the WHO considers it a major health threat. Alternative therapies for infection are urgently needed, therefore we have developed a novel drug class targeting a range of pathogens while retaining natural flora to restore microbiome homeostasis. Treatment of viral infections with glycopolymers Research Project | 1 Project MembersThe proposed project aims to develop a dual therapeutic approach to combat viral infections (with a focus on SARS-CoV-2) by preventing viral entry and dissemination. Firstly, by inhibiting trans-infection (mediated by DC SIGN) and secondly, by inhibiting initial viral attachment via heparan sulphate (HS) and related negatively charged epitopes on host cells. This can be achieved by presenting DC-SIGN ligands and HS subunits (or glycomimetics/analogues thereof) multivalently on a biodegradable scaffold to inhibit viral attachment and dissemination with high specificity and efficiency. Inspired by Nature: New Therapeutic Modalities to Control Adverse Complement & Coagulation Reactions in Immune and Thrombo-Inflammatory Conditions Research Project | 3 Project MembersThe 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. 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. 12 12
Design, synthesis, and evaluation of collectin-11 inhibitors for biomedical research and therapeutic development Research Project | 2 Project MembersImported from Grants Tool 4707200
Mucin O-glycans as regulators of pathogen virulence: glycan synthesis, mechanistic investigation, and therapeutic potential Research Project | 3 Project MembersImported from Grants Tool 4702942
Utilizing Factor H-Binding Peptides for the Protection of Xenotransplants from Complement-Mediated Damage Research Project | 1 Project MembersImported from Grants Tool 4705591
Helostasin - A Novel Complement Pathway Modulator Research Project | 4 Project MembersImported from Grants Tool 4702675
Leech-Derived Bivalent Peptide Inhibitors of Complement Initiating Proteases Research Project | 2 Project MembersImported from Grants Tool 4700693
ComplemenTED: An Integrated Platform for Complement Therapeutics Evaluation and Development Research Project | 1 Project MembersNo Description available
Development of glycan-based antimicrobial therapies Research Project | 3 Project MembersAntimicrobial resistance is reaching a global crisis and the WHO considers it a major health threat. Alternative therapies for infection are urgently needed, therefore we have developed a novel drug class targeting a range of pathogens while retaining natural flora to restore microbiome homeostasis.
Treatment of viral infections with glycopolymers Research Project | 1 Project MembersThe proposed project aims to develop a dual therapeutic approach to combat viral infections (with a focus on SARS-CoV-2) by preventing viral entry and dissemination. Firstly, by inhibiting trans-infection (mediated by DC SIGN) and secondly, by inhibiting initial viral attachment via heparan sulphate (HS) and related negatively charged epitopes on host cells. This can be achieved by presenting DC-SIGN ligands and HS subunits (or glycomimetics/analogues thereof) multivalently on a biodegradable scaffold to inhibit viral attachment and dissemination with high specificity and efficiency.
Inspired by Nature: New Therapeutic Modalities to Control Adverse Complement & Coagulation Reactions in Immune and Thrombo-Inflammatory Conditions Research Project | 3 Project MembersThe 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.
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.
