| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Hjortø, Gertrud M. Jarvis, Michael A. Jeppesen, Mads G. Dulal, Kalpana Zhu, Hua Cheng, Tong Spiess, Katja Garcia, K. Christopher Malmgaard-clausen, Mikkel Burg, John S. Rosenkilde, Mette M. Larsen, Olav Krzywkowski, Karen Kledal, Thomas N. |
| Description |
Author Affiliation: Spiess K ( INAGEN ApS., DK-2800 Kongens Lyngby, Denmark); Jeppesen MG ( INAGEN ApS., DK-2800 Kongens Lyngby, Denmark); Malmgaard-Clausen M ( INAGEN ApS., DK-2800 Kongens Lyngby, Denmark); Krzywkowski K ( INAGEN ApS., DK-2800 Kongens Lyngby, Denmark); Dulal K ( Department of Microbiology and Molecular Genetics, Rutgers-New Jersey Medical School, Newark, NJ 07184); Cheng T ( National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, Xiamen University, 361100 Fujian Province, China); Hjortø GM ( Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark); Larsen O ( Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark); Burg JS ( Stanford University School of Medicine, Stanford, CA 94305); Jarvis MA ( School of Biomedical and Healthcare Sciences, University of Plymouth, Plymouth PL4 8AA, United Kingdom.); Garcia KC ( Stanford University School of Medicine, Stanford, CA 94305); Zhu H ( Department of Microbiology and Molecular Genetics, Rutgers-New Jersey Medical School, Newark, NJ 07184); Kledal TN ( INAGEN ApS., DK-2800 Kongens Lyngby, Denmark); Rosenkilde MM ( Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark); |
| Abstract |
The use of receptor-ligand interactions to direct toxins to kill diseased cells selectively has shown considerable promise for treatment of a number of cancers and, more recently, autoimmune disease. Here we move the fusion toxin protein (FTP) technology beyond cancer/autoimmune therapeutics to target the human viral pathogen, human cytomegalovirus (HCMV), on the basis of its expression of the 7TM G protein-coupled chemokine receptor US28. The virus origin of US28 provides an exceptional chemokine-binding profile with high selectivity and improved binding for the CX3C chemokine, CX3CL1. Moreover, US28 is constitutively internalizing by nature, providing highly effective FTP delivery. We designed a synthetic CX3CL1 variant engineered to have ultra-high affinity for US28 and greater specificity for US28 than the natural sole receptor for CX3CL1, CX3CR1, and we fused the synthetic variant with the cytotoxic domain of Pseudomonas Exotoxin A. This novel strategy of a rationally designed FTP provided unparalleled anti-HCMV efficacy and potency in vitro and in vivo. |
| ISSN |
00278424 |
| e-ISSN |
10916490 |
| Journal |
Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number |
27 |
| Volume Number |
112 |
| Language |
English |
| Publisher |
National Academy of Sciences |
| Publisher Date |
2015-07-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Bacterial Proteins Metabolism Chemokine CX3CL1 Cytomegalovirus Infections Prevention & Control Receptors, Chemokine Antagonists & Inhibitors Recombinant Fusion Proteins Pharmacology Viral Proteins Genetics Cell Line Cell Survival Drug Effects Cytomegalovirus Physiology Virology Dose-Response Relationship, Drug Drug Design Fibroblasts HEK293 Cells Host-Pathogen Interactions Lung Cytology Protein Binding Time Factors Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Multidisciplinary |
