期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 27, 页码 8427-8432出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1509392112
关键词
HCMV; 7TM GPCR; protein engineering; antiviral drug; chemokine
资金
- Danish Research Council
- Novo Nordisk Foundation
- Lundbeck Foundation
- School of Biomedical and Healthcare Sciences, University of Plymouth
- NIH [NIH R01 GM097015]
- Cancer Research Institute
- Novo Nordisk Fonden [NNF12OC0001900] Funding Source: researchfish
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, CX(3)CL1. Moreover, US28 is constitutively internalizing by nature, providing highly effective FTP delivery. We designed a synthetic CX(3)CL1 variant engineered to have ultra-high affinity for US28 and greater specificity for US28 than the natural sole receptor for CX(3)CL1, CX(3)CR1, 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.
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