AI Article Synopsis
- - The study focuses on a new TLR7 agonist, UC-1V150, designed to minimize side effects associated with traditional TLR activators, which often cause excessive inflammation.
- - The modified UC-1V150, when combined with mouse serum albumin (MSA), showed to be significantly more potent at inducing cytokine production in immune cells, while also facilitating controlled local cytokine release in the lungs.
- - In tests on mice, the UC-1V150/MSA conjugate demonstrated promise as an immunotherapy by delaying mortality in models of pulmonary infections, suggesting it could be a safer and more effective treatment option.
Article Abstract
The immunotherapeutic activity of Toll-like receptor (TLR) activators has been difficult to exploit because of side effects related to the release and systemic dispersion of proinflammatory cytokines. To overcome this barrier, we have synthesized a versatile TLR7 agonist, 4-[6-amino-8-hydroxy-2-(2-methoxyethoxy)purin-9-ylmethyl]benzaldehyde (UC-1V150), bearing a free aldehyde that could be coupled to many different auxiliary chemical entities through a linker molecule with a hydrazine or amino group without any loss of activity. UC-1V150 was covalently coupled to mouse serum albumin (MSA) at a 5:1 molar ratio to yield a stable molecule with a characteristically altered UV spectrum. Compared with the unconjugated TLR7 agonist, the UC-1V150/MSA was a 10- to 100-fold more potent inducer of cytokine production in vitro by mouse bone marrow-derived macrophage and human peripheral blood mononuclear cells. When administrated to the lung, the conjugate induced a prolonged local release of cytokines at levels 10-fold or more higher than those found in serum. Under the same conditions, the untethered TLR7 ligand induced quick systemic cytokine release with resultant toxicity. In addition, two pulmonary infectious disease models were investigated wherein mice were pretreated with the conjugate and then challenged with either Bacillus anthracis spores or H1N1 influenza A virus. Significant delay in mortality was observed in both disease models with UC-1V150/MSA-pretreated mice, indicating the potential usefulness of the conjugate as a localized and targeted immunotherapeutic agent.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1820696 | PMC |
| http://dx.doi.org/10.1073/pnas.0611624104 | DOI Listing |
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