Activator for killers
Natural T-killer cells (iNKT) are a powerful weapon of the body against infections and a number of diseases: cancer, multiple sclerosis, systemic connective tissue diseases. The search for ways to activate iNKT in the future is aimed at developing new drugs against incurable diseases today.
In previous studies, several compounds activating iNKT were tested on mice, but they did not have sufficient effect on human cells.
An international group of immunologists, microbiologists and chemists led by Professor Amy Howell from the University of Connecticut reported on a new compound whose properties satisfy the needs of researchers.
We are talking about a modified version of the KRN7000 ligand synthesized earlier, which is able to selectively activate human iNKT and stimulate antitumor immunity by producing a specific protein cytokine Th1.
Unlike the new compound called AH10-7, KRN7000 molecules in human cell culture increased the production of both pro- and anti-inflammatory cytokines, and their contradictory action significantly weakened the desired effect.
Comparison of antitumor properties of KRN7000 and AH10-7.
Here and below are the drawings from an article in the journal Cell Chemical Biology.
AH10-7 differs from its predecessors by the addition of hydrocortic acid ester (hydrocinnamoyl ester), which made the compound more stable, and the absence of a sphingoid base, which contributed to the inconsistent release of cytokines. Such changes have enhanced the effectiveness of the entire molecular complex.
The detailed mechanism of interaction between AH10-7 and iNKT was tracked using X-ray diffraction analysis methods.
The new iNKT activator was tested first on wild mice and then on mouse models genetically modified to mimic human T-killers. In experiments on partially "humanized" mice, the new compound AH10-7 was at least as good as its predecessor KRN7000 in the effectiveness of iNKT cell activation.
Anticancer effect of iNKT activators. The upper row is the result of the treatment of melanoma in wild mice, the lower row is the result of genetically modified "humanized" mice. On the left – control (without treatment); in the middle – the result of treatment KRN7000; on the right – the result of treatment AH10-7.
AH10-7 is the result of many years of work, which began with computer modeling of possible interactions of molecules. The information received was a serious help for the development of the project. Today, the authors provide everyone interested with a detailed synthesis protocol so that they can continue studying and improving AH10-7.
Article by D. Chennamadhavuni et al. Dual Modifications of α-Galactosylceramide Synergize to Promote Activation of Human Invariant Natural Killer T Cells and Stimulate Anti-tumor Immunity is published in the journal Cell Chemical Biology.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru according to UConn Today: New Compound Helps Activate Cancer-Fighting T Cells.