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Biomedicines 2017, 5(1), 9; doi:10.3390/biomedicines5010009

Designing the Sniper: Improving Targeted Human Cytolytic Fusion Proteins for Anti-Cancer Therapy via Molecular Simulation

German Research School for Simulation Sciences, Forschungszentrum Jülich, Jülich 52425, Germany
Computational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich, Jülich 52425, Germany
Department of Physics, Rheinisch-Westfälische Technische Hochschule Aachen, Aachen 52062, Germany
Department of Integrative Biomedical Sciences, Institute for Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7701, South Africa
Scientific Computing Department, Science and Technology Facilities Council, Daresbury Laboratory, Warrington WA4 4AD, UK
JARA–HPC, Jülich Supercomputing Centre, Forschungszentrum Jülich GmbH, Jülich 52425, Germany
Authors to whom correspondence should be addressed.
Academic Editor: Shaker A. Mousa
Received: 30 December 2016 / Revised: 27 January 2017 / Accepted: 10 February 2017 / Published: 17 February 2017
(This article belongs to the Special Issue Targeted Human Cytolytic Fusion Proteins)
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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. View Full-Text
Keywords: immunotherapy; targeted human cytolytic fusion proteins; molecular dynamics; high performance computing; Angiogenin; Granzyme B immunotherapy; targeted human cytolytic fusion proteins; molecular dynamics; high performance computing; Angiogenin; Granzyme B

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Bochicchio, A.; Jordaan, S.; Losasso, V.; Chetty, S.; Perera, R.C.; Ippoliti, E.; Barth, S.; Carloni, P. Designing the Sniper: Improving Targeted Human Cytolytic Fusion Proteins for Anti-Cancer Therapy via Molecular Simulation. Biomedicines 2017, 5, 9.

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