Designing the Sniper: Improving Targeted Human Cytolytic Fusion Proteins for Anti-Cancer Therapy via Molecular Simulation
Targeted human cytolytic fusion proteins (hCFPs) are humanized immunotoxins for selective treatment of different diseases including cancer. They are composed of a ligand specifically binding to target cells genetically linked to a human apoptosis-inducing enzyme. hCFPs target cancer cells via an ant...
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| Format: | Article |
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MDPI AG
2017-02-01
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| Series: | Biomedicines |
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| Online Access: | http://www.mdpi.com/2227-9059/5/1/9 |
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| author | Anna Bochicchio Sandra Jordaan Valeria Losasso Shivan Chetty Rodrigo Casasnovas Perera Emiliano Ippoliti Stefan Barth Paolo Carloni |
| author_facet | Anna Bochicchio Sandra Jordaan Valeria Losasso Shivan Chetty Rodrigo Casasnovas Perera Emiliano Ippoliti Stefan Barth Paolo Carloni |
| author_sort | Anna Bochicchio |
| collection | DOAJ |
| description | Targeted human cytolytic fusion proteins (hCFPs) are humanized immunotoxins for selective treatment of different diseases including cancer. They are composed of a ligand specifically binding to target cells genetically linked to a human apoptosis-inducing enzyme. hCFPs target cancer cells via an antibody or derivative (scFv) specifically binding to e.g., tumor associated antigens (TAAs). After internalization and translocation of the enzyme from endocytosed endosomes, the human enzymes introduced into the cytosol are efficiently inducing apoptosis. Under in vivo conditions such enzymes are subject to tight regulation by native inhibitors in order to prevent inappropriate induction of cell death in healthy cells. Tumor cells are known to upregulate these inhibitors as a survival mechanism resulting in escape of malignant cells from elimination by immune effector cells. Cytosolic inhibitors of Granzyme B and Angiogenin (Serpin P9 and RNH1, respectively), reduce the efficacy of hCFPs with these enzymes as effector domains, requiring detrimentally high doses in order to saturate inhibitor binding and rescue cytolytic activity. Variants of Granzyme B and Angiogenin might feature reduced affinity for their respective inhibitors, while retaining or even enhancing their catalytic activity. A powerful tool to design hCFPs mutants with improved potency is given by in silico methods. These include molecular dynamics (MD) simulations and enhanced sampling methods (ESM). MD and ESM allow predicting the enzyme-protein inhibitor binding stability and the associated conformational changes, provided that structural information is available. Such “high-resolution” detailed description enables the elucidation of interaction domains and the identification of sites where particular point mutations may modify those interactions. This review discusses recent advances in the use of MD and ESM for hCFP development from the viewpoints of scientists involved in both fields. |
| first_indexed | 2024-12-21T07:48:01Z |
| format | Article |
| id | doaj.art-84a6e6881deb49c7ace63c399f423782 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-12-21T07:48:01Z |
| publishDate | 2017-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-84a6e6881deb49c7ace63c399f4237822022-12-21T19:11:09ZengMDPI AGBiomedicines2227-90592017-02-0151910.3390/biomedicines5010009biomedicines5010009Designing the Sniper: Improving Targeted Human Cytolytic Fusion Proteins for Anti-Cancer Therapy via Molecular SimulationAnna Bochicchio0Sandra Jordaan1Valeria Losasso2Shivan Chetty3Rodrigo Casasnovas Perera4Emiliano Ippoliti5Stefan Barth6Paolo Carloni7German Research School for Simulation Sciences, Forschungszentrum Jülich, Jülich 52425, GermanyDepartment of Integrative Biomedical Sciences, Institute for Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7701, South AfricaScientific Computing Department, Science and Technology Facilities Council, Daresbury Laboratory, Warrington WA4 4AD, UKDepartment of Integrative Biomedical Sciences, Institute for Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7701, South AfricaComputational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich, Jülich 52425, GermanyComputational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich, Jülich 52425, GermanyDepartment of Integrative Biomedical Sciences, Institute for Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7701, South AfricaComputational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich, Jülich 52425, GermanyTargeted human cytolytic fusion proteins (hCFPs) are humanized immunotoxins for selective treatment of different diseases including cancer. They are composed of a ligand specifically binding to target cells genetically linked to a human apoptosis-inducing enzyme. hCFPs target cancer cells via an antibody or derivative (scFv) specifically binding to e.g., tumor associated antigens (TAAs). After internalization and translocation of the enzyme from endocytosed endosomes, the human enzymes introduced into the cytosol are efficiently inducing apoptosis. Under in vivo conditions such enzymes are subject to tight regulation by native inhibitors in order to prevent inappropriate induction of cell death in healthy cells. Tumor cells are known to upregulate these inhibitors as a survival mechanism resulting in escape of malignant cells from elimination by immune effector cells. Cytosolic inhibitors of Granzyme B and Angiogenin (Serpin P9 and RNH1, respectively), reduce the efficacy of hCFPs with these enzymes as effector domains, requiring detrimentally high doses in order to saturate inhibitor binding and rescue cytolytic activity. Variants of Granzyme B and Angiogenin might feature reduced affinity for their respective inhibitors, while retaining or even enhancing their catalytic activity. A powerful tool to design hCFPs mutants with improved potency is given by in silico methods. These include molecular dynamics (MD) simulations and enhanced sampling methods (ESM). MD and ESM allow predicting the enzyme-protein inhibitor binding stability and the associated conformational changes, provided that structural information is available. Such “high-resolution” detailed description enables the elucidation of interaction domains and the identification of sites where particular point mutations may modify those interactions. This review discusses recent advances in the use of MD and ESM for hCFP development from the viewpoints of scientists involved in both fields.http://www.mdpi.com/2227-9059/5/1/9immunotherapytargeted human cytolytic fusion proteinsmolecular dynamicshigh performance computingAngiogeninGranzyme B |
| spellingShingle | Anna Bochicchio Sandra Jordaan Valeria Losasso Shivan Chetty Rodrigo Casasnovas Perera Emiliano Ippoliti Stefan Barth Paolo Carloni Designing the Sniper: Improving Targeted Human Cytolytic Fusion Proteins for Anti-Cancer Therapy via Molecular Simulation Biomedicines immunotherapy targeted human cytolytic fusion proteins molecular dynamics high performance computing Angiogenin Granzyme B |
| title | Designing the Sniper: Improving Targeted Human Cytolytic Fusion Proteins for Anti-Cancer Therapy via Molecular Simulation |
| title_full | Designing the Sniper: Improving Targeted Human Cytolytic Fusion Proteins for Anti-Cancer Therapy via Molecular Simulation |
| title_fullStr | Designing the Sniper: Improving Targeted Human Cytolytic Fusion Proteins for Anti-Cancer Therapy via Molecular Simulation |
| title_full_unstemmed | Designing the Sniper: Improving Targeted Human Cytolytic Fusion Proteins for Anti-Cancer Therapy via Molecular Simulation |
| title_short | Designing the Sniper: Improving Targeted Human Cytolytic Fusion Proteins for Anti-Cancer Therapy via Molecular Simulation |
| title_sort | designing the sniper improving targeted human cytolytic fusion proteins for anti cancer therapy via molecular simulation |
| topic | immunotherapy targeted human cytolytic fusion proteins molecular dynamics high performance computing Angiogenin Granzyme B |
| url | http://www.mdpi.com/2227-9059/5/1/9 |
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