Journal article
Rationally designed chemokine-based toxin targeting the viral G protein-coupled receptor US28 potently inhibits cytomegalovirus infection in vivo
Inagen ApS1
Rutgers New Jersey Medical School2
Xiamen University3
University of Copenhagen4
Stanford University School of Medicine5
University of Plymouth6
National Veterinary Institute, Technical University of Denmark7
Section for Virology, National Veterinary Institute, Technical University of Denmark8
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.
Language: | English |
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Publisher: | National Academy of Sciences |
Year: | 2015 |
Pages: | 8427-8432 |
ISSN: | 10916490 and 00278424 |
Types: | Journal article |
DOI: | 10.1073/pnas.1509392112 |
ORCIDs: | 0000-0001-9600-3254 |
7TM GPCR Bacterial Proteins Cell Line Cell Survival Chemokine CX3CL1 Cytomegalovirus Cytomegalovirus Infections Dose-Response Relationship, Drug Drug Design Fibroblasts HCMV HEK293 Cells Host-Pathogen Interactions Humans Lung Protein Binding Receptors, Chemokine Recombinant Fusion Proteins Time Factors US28 receptor, Cytomegalovirus Viral Proteins antiviral drug chemokine protein engineering pseudomonas exoprotein A protein, Pseudomonas aeruginosa