In vivo protection provided by a synthetic new alpha-galactosyl ceramide analog against bacterial and viral infections in murine models.
Alpha-galactosyl ceramide (α-GalCer) has been known to bind to the CD1d receptor on dendritic cells and activate invariant natural killer T (iNKT) cells, which subsequently secrete T-helper-cell 1 (Th1) and Th2 cytokines, which correlate with anti-infection activity and the prevention of autoimmune diseases, respectively. α-GalCer elicits the secretion of these two cytokines nonselectively, and thus, its effectiveness is limited by the opposing effects of the Th1 and Th2 cytokines. Reported here is the synthesis of a new α-GalCer analog (compound C34), based on the structure of CD1d, with a 4-(4-fluorophenoxy) phenyl undecanoyl modification of the N-acyl moiety of α-GalCer. Using several murine bacterial and viral infection models, we demonstrated that C34 has superior antibacterial and antiviral activities in comparison with those of several other Th1-selective glycolipids and that it is most effective by administering it to mice in a prophylactic manner before or shortly after infection.
Lin
Kun-Hsien
KH
Genomics Research Center, Academia Sinica, Nankang District, Taipei, Taiwan.
Liang
Jian-Jong
JJ
Huang
Wen-I
WI
Lin-Chu
Shao-Ying
SY
Su
Ching-Yao
CY
Lee
Yi-Ling
YL
Jan
Jia-Tsong
JT
Lin
Yi-Ling
YL
Cheng
Yih-Shyun E
YS
Wong
Chi-Huey
CH
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D005699:Galactosylceramides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D020578:Sphingomonas / Q000187:drug effects* / Q000472:pathogenicity; D013211:Staphylococcus aureus / Q000187:drug effects / Q000472:pathogenicity
D000900:Anti-Bacterial Agents; D005699:Galactosylceramides; C493154:alpha-galactosylceramide